Mitochondrial Dysfunction in Aging: Future Therapies and Precision Medicine Approaches
Lanlan Jia,
Ziyu Wei,
Jinyuan Luoqian,
Xi Wang,
Chao Huang,
Corresponding Author
Lanlan Jia
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, China
Correspondence: Lanlan Jia ([email protected])
Chao Huang ([email protected])
Search for more papers by this authorZiyu Wei
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Search for more papers by this authorJinyuan Luoqian
Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, China
Search for more papers by this authorXi Wang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
Search for more papers by this authorCorresponding Author
Chao Huang
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, China
Correspondence: Lanlan Jia ([email protected])
Chao Huang ([email protected])
Search for more papers by this authorLanlan Jia,
Ziyu Wei,
Jinyuan Luoqian,
Xi Wang,
Chao Huang,
Corresponding Author
Lanlan Jia
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, China
Correspondence: Lanlan Jia ([email protected])
Chao Huang ([email protected])
Search for more papers by this authorZiyu Wei
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Search for more papers by this authorJinyuan Luoqian
Translational Medicine Research Center, Guizhou Medical University, Guiyang, Guizhou, China
Search for more papers by this authorXi Wang
Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
Search for more papers by this authorCorresponding Author
Chao Huang
Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Chengdu, China
Correspondence: Lanlan Jia ([email protected])
Chao Huang ([email protected])
Search for more papers by this authorFirst published: 17 July 2025
Lanlan Jia and Ziyu Wei contributed equally to this study.
ABSTRACT
Mitochondria are the primary energy hubs of cells and are critical for maintaining cellular functions. However, aging leads to a decline in mitochondrial efficiency. This decline is marked by increased reactive oxygen species, accumulation of mitochondrial DNA mutations, impaired oxidative phosphorylation, and breakdown of mitochondrial quality control systems. Such changes are associated with the development of neurodegenerative, cardiovascular, and metabolic diseases. Although much research has been done, the precise connection between mitochondrial dysfunction and aging remains unclear. Furthermore, current literature exhibits a lack of systematic organization regarding the mitochondria-targeted therapeutic interventions. This review systematically explores the mechanisms underlying mitochondrial deterioration during aging. Key focuses include impaired biogenesis, disrupted dynamics, dysregulated stress responses, and defective clearance of damaged mitochondria. Additionally, this review explores innovative therapeutic strategies for these mitochondrial problems, including a combination of nanodelivery systems, artificially intelligent drug-screening techniques, and cutting-edge tools, such as CRISPR/Cas9 gene editing. By integrating recent advances in mitochondrial biology, this review provides a comprehensive framework that bridges basic mechanisms with clinical applications. The insights presented here underscore the potential of precision mitochondrial medicine as a novel approach to combating age-related disorders, enhancing our capacity to address age-related diseases, and foster healthy aging.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The authors have nothing to report.
References
- 1M. Padeiro, P. Santana, and M. Grant, “ Chapter 1—Global Aging and Health Determinants in a Changing World,” in Aging, eds. P. J. Oliveira and J. O. Malva (Academic Press, 2023), 3–30.
10.1016/B978-0-12-823761-8.00021-5 Google Scholar
- 2J. Guo, X. Huang, L. Dou, et al., “Aging and Aging-Related Diseases: From Molecular Mechanisms to Interventions and Treatments,” Signal Transduction and Targeted Therapy 7, no. 1 (2022): 391.
- 3J. A. Amorim, G. Coppotelli, A. P. Rolo, C. M. Palmeira, J. M. Ross, and D. A. Sinclair, “Mitochondrial and Metabolic Dysfunction in Ageing and Age-Related Diseases,” Nature Reviews Endocrinology 18, no. 4 (2022): 243–258.
- 4N. Sun, R. J. Youle, and T. Finkel, “The Mitochondrial Basis of Aging,” Molecular Cell 61, no. 5 (2016): 654–666.
- 5R. K. Lane, T. Hilsabeck, and S. L. Rea, “The Role of Mitochondrial Dysfunction in Age-Related Diseases,” Biochimica et Biophysica Acta (BBA)—Bioenergetics 1847, no. 11 (2015): 1387–1400.
- 6O. A. Zhunina, N. G. Yabbarov, A. V. Grechko, et al., “The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes,” Frontiers in Molecular Biosciences 8 (2021): 671908.
- 7J. F. Passos, G. Saretzki, S. Ahmed, et al., “Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence,” PLoS Biology 5, no. 5 (2007): e110.
- 8J. F. Passos, G. Nelson, C. Wang, et al., “Feedback Between p21 and Reactive Oxygen Production Is Necessary for Cell Senescence,” Molecular Systems Biology 6 (2010): 347.
- 9G. Nelson, O. Kucheryavenko, J. Wordsworth, and T. von Zglinicki, “The Senescent Bystander Effect Is Caused by ROS-Activated NF-κB Signalling,” Mechanisms of Ageing and Development 170 (2018): 30–36.
- 10R. Di Micco, M. Fumagalli, A. Cicalese, et al., “Oncogene-Induced Senescence Is a DNA Damage Response Triggered by DNA Hyper-Replication,” Nature 444, no. 7119 (2006): 638–642.
- 11C. Correia-Melo, F. D. Marques, R. Anderson, et al., “Mitochondria Are Required for Pro-Ageing Features of the Senescent Phenotype,” EMBO Journal 35, no. 7 (2016): 724–742.
- 12T. Fu, W. Sun, J. Xue, et al., “Proteolytic Rewiring of Mitochondria by LONP1 Directs Cell Identity Switching of Adipocytes,” Nature Cell Biology 25, no. 6 (2023): 848–864.
- 13L. Zhu, Q. Zhou, L. He, and L. Chen, “Mitochondrial Unfolded Protein Response: An Emerging Pathway in Human Diseases,” Free Radical Biology and Medicine 163 (2021): 125–134.
- 14M. Y. W. Ng, T. Wai, and A. Simonsen, “Quality Control of the Mitochondrion,” Developmental Cell 56, no. 7 (2021): 881–905.
- 15A. Rana, M. P. Oliveira, A. V. Khamoui, et al., “Promoting Drp1-Mediated Mitochondrial Fission in Midlife Prolongs Healthy Lifespan of Drosophila melanogaster,” Nature Communications 8 (2017): 448.
- 16M. Gonzalez-Freire, A. Diaz-Ruiz, D. Hauser, et al., “The Road Ahead for Health and Lifespan Interventions,” Ageing Research Reviews 59 (2020): 101037.
- 17D. C. Wallace, “A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine,” Annual Review of Genetics 39 (2005): 359–407.
- 18E. Rodríguez-Bies, B. T. Tung, P. Navas, and G. López-Lluch, “Resveratrol Primes the Effects of Physical Activity in Old Mice,” British Journal of Nutrition 116, no. 6 (2016): 979–988.
- 19M. J. Uddin, M. Farjana, A. Moni, K. S. Hossain, M. A. Hannan, and H. Ha, “Prospective Pharmacological Potential of Resveratrol in Delaying Kidney Aging,” International Journal of Molecular Sciences 22, no. 15 (2021): 8258.
- 20I. Mohammed, M. D. Hollenberg, H. Ding, and C. R. Triggle, “A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan,” Frontiers in Endocrinology 12 (2021): 718942.
- 21J. J. Reid, M. A. Linden, F. F. Peelor, R. A. Miller, K. L. Hamilton, and B. F. Miller, “Brain Protein Synthesis Rates in the UM-HET3 Mouse Following Treatment With Rapamycin or Rapamycin With Metformin,” Journals of Gerontology: Series A 75, no. 1 (2020): 40–49.
- 22M. Capristo, V. Del Dotto, C. V. Tropeano, et al., “Rapamycin Rescues Mitochondrial Dysfunction in Cells Carrying the m.8344A > G Mutation in the mitochondrial tRNALys,” Molecular Medicine 28, no. 1 (2022): 90.
- 23A. Bratic and N. G. Larsson, “The Role of Mitochondria in Aging,” Journal of Clinical Investigation 123, no. 3 (2013): 951–957.
- 24J. Yang, J. Luo, X. Tian, Y. Zhao, Y. Li, and X. Wu, “Progress in Understanding Oxidative Stress, Aging, and Aging-Related Diseases,” Antioxidants 13, no. 4 (2024): 394.
- 25N. G. Larsson, J. Wang, H. Wilhelmsson, et al., “Mitochondrial Transcription Factor A Is Necessary for mtDNA Maintance and Embryogenesis in Mice,” Nature Genetics 18, no. 3 (1998): 231–236.
- 26J. W. Taanman, “The Mitochondrial Genome: Structure, Transcription, Translation and Replication,” Biochimica et Biophysica Acta (BBA)—Bioenergetics 1410, no. 2 (1999): 103–123.
- 27G. Lenaz, C. Bovina, C. Castelluccio, et al., “Mitochondrial Complex I Defects in Aging,” Molecular and Cellular Biochemistry 174, no. 1–2 (1997): 329–333.
- 28H. Tauchi and T. Sato, “Age Changes in Size and Number of Mitochondria of Human Hepatic Cells,” Journal of Gerontology 23, no. 4 (1968): 454–461.
- 29A. M. Wolf, “mtDNA Mutations and Aging—Not a Closed Case After All?,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 56.
- 30K. J. Ahlqvist, R. H. Hämäläinen, S. Yatsuga, et al., “Somatic Progenitor Cell Vulnerability to Mitochondrial DNA Mutagenesis Underlies Progeroid Phenotypes in Polg Mutator Mice,” Cell Metabolism 15, no. 1 (2012): 100–109.
- 31C. G. Fraga, M. K. Shigenaga, J. W. Park, P. Degan, and B. N. Ames, “Oxidative Damage to DNA During Aging: 8-hydroxy-2′-deoxyguanosine in Rat Organ DNA and Urine,” Proceedings of the National Academy of Sciences 87, no. 12 (1990): 4533–4537.
- 32E. R. Stadtman, “Protein Oxidation and Aging,” Science 257, no. 5074 (1992): 1220–1224.
- 33L. J. Marnett, H. K. Hurd, M. C. Hollstein, D. E. Levin, H. Esterbauer, and B. N. Ames, “Naturally Occurring Carbonyl Compounds Are Mutagens Salmonella Tester Strain TA104,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 148, no. 1–2 (1985): 25–34.
- 34Y. H. Wei and H. C. Lee, “Oxidative Stress, Mitochondrial DNA Mutation, and Impairment of Antioxidant Enzymes in Aging,” Experimental Biology and Medicine 227, no. 9 (2002): 671–682.
- 35D. Bakula and M. Scheibye-Knudsen, “MitophAging: Mitophagy in Aging and Disease,” Frontiers in Cell and Developmental Biology 8 (2020): 239.
- 36Z. Wang, Y. Sun, Z. Bai, M. Li, D. Kong, and G. Wu, “Mitochondria-Related Genome-Wide Mendelian Randomization Identifies Putatively Causal Genes for Neurodegenerative Diseases,” Movement Disorders 40 (2025): 693–703.
- 37Y. Guo, T. Guan, K. Shafiq, et al., “Mitochondrial Dysfunction in Aging,” Ageing Research Reviews 88 (2023): 101955.
- 38R. M. Levytskyy, E. M. Germany, and O. Khalimonchuk, “Mitochondrial Quality Control Proteases in Neuronal Welfare,” Journal of Neuroimmune Pharmacology 11, no. 4 (2016): 629–644.
- 39A. Picca, F. Guerra, R. Calvani, et al., “Mitochondrial-Derived Vesicles in Skeletal Muscle Remodeling and Adaptation,” Seminars in Cell & Developmental Biology 143 (2023): 37–45.
- 40S. B. Larsen, Z. Hanss, and R. Krüger, “The Genetic Architecture of Mitochondrial Dysfunction in Parkinson's Disease,” Cell and Tissue Research 373, no. 1 (2018): 21–37.
- 41A. Picca, R. T. Mankowski, J. L. Burman, et al., “Mitochondrial Quality Control Mechanisms as Molecular Targets in Cardiac Ageing,” Nature Reviews Cardiology 15, no. 9 (2018): 543–554.
- 42R. C. Scarpulla, “Metabolic Control of Mitochondrial Biogenesis Through the PGC-1 Family Regulatory Network,” Biochimica et Biophysica Acta (BBA)—Molecular Cell Research 1813, no. 7 (2011): 1269–1278.
- 43Y. Li, X. Tian, J. Luo, T. Bao, S. Wang, and X. Wu, “Molecular Mechanisms of Aging and Anti-Aging Strategies,” Cell Communication and Signaling 22, no. 1 (2024): 285.
- 44S. Kong, B. Cai, and Q. Nie, “PGC-1α Affects Skeletal Muscle and Adipose Tissue Development by Regulating Mitochondrial Biogenesis,” Molecular Genetics and Genomics 297, no. 3 (2022): 621–633.
- 45L. Giovannini and S. Bianchi, “Role of Nutraceutical SIRT1 Modulators in AMPK and mTOR Pathway: Evidence of a Synergistic Effect,” Nutrition 34 (2017): 82–96.
- 46Z. Wu, P. Puigserver, U. Andersson, et al., “Mechanisms Controlling Mitochondrial Biogenesis and Respiration Through the Thermogenic Coactivator PGC-1,” Cell 98, no. 1 (1999): 115–124.
- 47C. Chen, Y. I. N. Yuan-yuan, W. U. Xia-fang, et al., “Advance in Researches on Role of Mapk and PI3K/AKT Pathways in ROS-Induced Activation of Nuclear Factor Erythroid 2-Related Factor 2,” Chinese Journal of Public Health 32, no. 6 (2016): 870–873.
- 48E. R. Chin, “The Role of Calcium and Calcium/Calmodulin-Dependent Kinases in Skeletal Muscle Plasticity and Mitochondrial Biogenesis,” Proceedings of the Nutrition Society 63, no. 2 (2004): 279–286.
- 49M. Chen, R. Yan, J. Luo, J. Ning, R. Zhou, and L. Ding, “The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons,” Neurochemical Research 48, no. 9 (2023): 2595–2606.
- 50J. R. Friedman, L. L. Lackner, M. West, J. R. DiBenedetto, J. Nunnari, and G. K. Voeltz, “ER Tubules Mark Sites of Mitochondrial Division,” Science 334, no. 6054 (2011): 358–362.
- 51H. Chen, S. A. Detmer, A. J. Ewald, E. E. Griffin, S. E. Fraser, and D. C. Chan, “Mitofusins Mfn1 and Mfn2 Coordinately Regulate Mitochondrial Fusion and Are Essential for Embryonic Development,” Journal of Cell Biology 160, no. 2 (2003): 189–200.
- 52M. J. Baker, P. A. Lampe, D. Stojanovski, et al., “Stress-Induced OMA1 Activation and Autocatalytic Turnover Regulate OPA1-Dependent Mitochondrial Dynamics,” EMBO Journal 33, no. 6 (2014): 578–593.
- 53A. Brocchi, E. Rebelos, A. Dardano, M. Mantuano, and G. Daniele, “Effects of Intermittent Fasting on Brain Metabolism,” Nutrients 14, no. 6 (2022): 1275.
- 54F. Torma, Z. Gombos, M. Jokai, M. Takeda, T. Mimura, and Z. Radak, “High Intensity Interval Training and Molecular Adaptive Response of Skeletal Muscle,” Sports Medicine and Health Science 1, no. 1 (2019): 24–32.
- 55H. Y. Lin, S. W. Weng, Y. H. Chang, et al., “The Causal Role of Mitochondrial Dynamics in Regulating Insulin Resistance in Diabetes: Link Through Mitochondrial Reactive Oxygen Species,” Oxidative Medicine and Cellular Longevity 2018 (2018): 7514383.
- 56W. Song, J. Chen, A. Petrilli, et al., “Mutant Huntingtin Binds the Mitochondrial Fission GTPase Dynamin-Related Protein-1 and Increases Its Enzymatic Activity,” Nature Medicine 17, no. 3 (2011): 377–382.
- 57U. Shirendeb, A. P. Reddy, M. Manczak, et al., “Abnormal Mitochondrial Dynamics, Mitochondrial Loss and Mutant Huntingtin Oligomers in Huntington's Disease: Implications for Selective Neuronal Damage,” Human Molecular Genetics 20, no. 7 (2011): 1438–1455.
- 58X. Wang, B. Su, H. Lee, et al., “Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease,” Journal of Neuroscience 29, no. 28 (2009): 9090–9103.
- 59D. H. Cho, T. Nakamura, J. Fang, et al., “S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury,” Science 324, no. 5923 (2009): 102–105.
- 60P. Portz and M. K. Lee, “Changes in Drp1 Function and Mitochondrial Morphology Are Associated With the α-Synuclein Pathology in a Transgenic Mouse Model of Parkinson's Disease,” Cells 10, no. 4 (2021): 885.
- 61T. Petrozziello, E. A. Bordt, A. N. Mills, et al., “Targeting Tau Mitigates Mitochondrial Fragmentation and Oxidative Stress in Amyotrophic Lateral Sclerosis,” Molecular Neurobiology 59, no. 1 (2022): 683–702.
- 62J. Stein, B. Walkenfort, H. Cihankaya, et al., “Increased ROS-Dependent Fission of Mitochondria Causes Abnormal Morphology of the Cell Powerhouses in a Murine Model of Amyotrophic Lateral Sclerosis,” Oxidative Medicine and Cellular Longevity 2021 (2021): 6924251.
- 63Y. Wang, Y. Li, X. Jiang, et al., “OPA1 Supports Mitochondrial Dynamics and Immune Evasion to CD8(+) T Cell in Lung Adenocarcinoma,” PeerJ 10 (2022): e14543.
- 64L. Fu, Q. Dong, J. He, et al., “SIRT4 Inhibits Malignancy Progression of NSCLCs, Through Mitochondrial Dynamics Mediated by the ERK-Drp1 Pathway,” Oncogene 36, no. 19 (2017): 2724–2736.
- 65L. Chen, Q. Gong, J. P. Stice, and A. A. Knowlton, “Mitochondrial OPA1, Apoptosis, and Heart Failure,” Cardiovascular Research 84, no. 1 (2009): 91–99.
- 66L. Guan, Z. Che, X. Meng, et al., “MCU Up-Regulation Contributes to Myocardial Ischemia-Reperfusion Injury Through Calpain/OPA-1-Mediated Mitochondrial Fusion/Mitophagy Inhibition,” Journal of Cellular and Molecular Medicine 23, no. 11 (2019): 7830–7843.
- 67L. Hu, M. Ding, D. Tang, et al., “Targeting Mitochondrial Dynamics by Regulating Mfn2 for Therapeutic Intervention in Diabetic Cardiomyopathy,” Theranostics 9, no. 13 (2019): 3687–3706.
- 68J. J. Ryan, G. Marsboom, Y. H. Fang, et al., “PGC1α-Mediated Mitofusin-2 Deficiency in Female Rats and Humans With Pulmonary Arterial Hypertension,” American Journal of Respiratory and Critical Care Medicine 187, no. 8 (2013): 865–878.
- 69J. Abu-Hanna, E. Anastasakis, J. A. Patel, et al., “Prostacyclin Mimetics Inhibit DRP1-Mediated Pro-Proliferative Mitochondrial Fragmentation in Pulmonary Arterial Hypertension,” Vascular pharmacology 151 (2023): 107194.
- 70G. P. Eckert, C. Schiborr, S. Hagl, et al., “Curcumin Prevents Mitochondrial Dysfunction in the Brain of the Senescence-Accelerated Mouse-Prone 8,” Neurochemistry International 62, no. 5 (2013): 595–602.
- 71Y. Hong, H. He, G. Jiang, et al., “miR-155-5p Inhibition Rejuvenates Aged Mesenchymal Stem Cells and Enhances Cardioprotection Following Infarction,” Aging Cell 19, no. 4 (2020): e13128.
- 72H. He, B. Yu, Z. Liu, et al., “Vascular Progenitor Cell Senescence in Patients With Marfan Syndrome,” Journal of Cellular and Molecular Medicine 23, no. 6 (2019): 4139–4152.
- 73T. Shpilka and C. M. Haynes, “The Mitochondrial UPR: Mechanisms, Physiological Functions and Implications in Ageing,” Nature Reviews Molecular Cell Biology 19, no. 2 (2018): 109–120.
- 74L. Ruan, C. Zhou, E. Jin, et al., “Cytosolic Proteostasis Through Importing of Misfolded Proteins into Mitochondria,” Nature 543, no. 7645 (2017): 443–446.
- 75A. B. Harbauer, R. P. Zahedi, A. Sickmann, N. Pfanner, and C. Meisinger, “The Protein Import Machinery of Mitochondria—A Regulatory Hub in Metabolism, Stress, and Disease,” Cell Metabolism 19, no. 3 (2014): 357–372.
- 76H. Itoh, A. Komatsuda, H. Ohtani, et al., “Mammalian HSP60 Is Quickly Sorted into the Mitochondria under Conditions of Dehydration,” European Journal of Biochemistry 269, no. 23 (2002): 5931–5938.
- 77K. Okamoto, “The Protein Import Motor of Mitochondria: A Targeted Molecular Ratchet Driving Unfolding and Translocation,” EMBO Journal 21, no. 14 (2002): 3659–3671.
- 78B. F. Teske, M. E. Fusakio, D. Zhou, et al., “CHOP Induces Activating Transcription Factor 5 (ATF5) to Trigger Apoptosis in Response to Perturbations in Protein Homeostasis,” Molecular Biology of the Cell 24, no. 15 (2013): 2477–2490.
- 79C. J. Fiorese, A. M. Schulz, Y. F. Lin, N. Rosin, M. W. Pellegrino, and C. M. Haynes, “The Transcription Factor ATF5 Mediates a Mammalian Mitochondrial UPR,” Current Biology 26, no. 15 (2016): 2037–2043.
- 80C. Münch, “The Different Axes of the Mammalian Mitochondrial Unfolded Protein Response,” BMC Biology 16, no. 1 (2018): 81.
- 81H.-G. Goo, H. Rhim, and S. Kang, “HtrA2/Omi Influences the Stability of LON Protease 1 and Prohibitin, Proteins Involved in Mitochondrial Homeostasis,” Experimental Cell Research 328, no. 2 (2014): 456–465.
- 82D. Hu, X. Sun, X. Liao, et al., “Alpha-Synuclein Suppresses Mitochondrial Protease ClpP to Trigger Mitochondrial Oxidative Damage and Neurotoxicity,” Acta Neuropathologica 137, no. 6 (2019): 939–960.
- 83S. C. Pino, B. O'sullivan-Murphy, E. A. Lidstone, et al., “CHOP Mediates Endoplasmic Reticulum Stress-Induced Apoptosis in Gimap5-Deficient T Cells,” PLoS ONE 4, no. 5 (2009): e5468.
- 84D. Y. Li, J. L. Wu, L. L. Luo, et al., “Role of c-Jun N-Terminal Kinase-Mediated FOXO3a Nuclear Translocation in Neuronal Apoptosis in Neonatal Rats With Hypoxic–Ischemic Brain Damage,” Zhongguo dang dai er ke za zhi = Chinese Journal of Contemporary Pediatrics 19, no. 4 (2017): 458–462.
- 85H. Tang, R. Kang, J. Liu, and D. Tang, “ATF4 in Cellular Stress, Ferroptosis, and Cancer,” Archives of Toxicology 98, no. 4 (2024): 1025–1041.
- 86K. Palikaras, E. Lionaki, and N. Tavernarakis, “Mechanisms of Mitophagy in Cellular Homeostasis, Physiology and Pathology,” Nature Cell Biology 20, no. 9 (2018): 1013–1022.
- 87C. López-Otín, M. A. Blasco, L. Partridge, M. Serrano, and G. Kroemer, “Hallmarks of Aging: An Expanding Universe,” Cell 186, no. 2 (2023): 243–278.
- 88D. J. Tyrrell, M. G. Blin, J. Song, S. C. Wood, and D. R. Goldstein, “Aging Impairs Mitochondrial Function and Mitophagy and Elevates Interleukin 6 Within the Cerebral Vasculature,” Journal of the American Heart Association 9, no. 23 (2020): e017820.
- 89C. Gladkova, S. L. Maslen, J. M. Skehel, and D. Komander, “Mechanism of Parkin Activation by PINK1,” Nature 559, no. 7714 (2018): 410–414.
- 90E. M. Fivenson, S. Lautrup, N. Sun, et al., “Mitophagy in Neurodegeneration and Aging,” Neurochemistry International 109 (2017): 202–209.
- 91S. Pickles, P. Vigié, and R. J. Youle, “Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance,” Current Biology 28, no. 4 (2018): R170–R185.
- 92M. Lazarou, D. A. Sliter, L. A. Kane, et al., “The Ubiquitin Kinase PINK1 Recruits Autophagy Receptors to Induce Mitophagy,” Nature 524, no. 7565 (2015): 309–314.
- 93Y. C. Wong and E. L. F. Holzbaur, “Optineurin Is an Autophagy Receptor for Damaged Mitochondria in Parkin-Mediated Mitophagy That Is Disrupted by an ALS-Linked Mutation,” Proceedings of the National Academy of Sciences 111, no. 42 (2014): E4439–E4448.
- 94R. Q. Yao, C. Ren, Z. F. Xia, and Y. M. Yao, “Organelle-Specific Autophagy in Inflammatory Diseases: A Potential Therapeutic Target Underlying the Quality Control of Multiple Organelles,” Autophagy 17, no. 2 (2021): 385–401.
- 95J. Oh, C. K. Youn, Y. Jun, E. R. Jo, and S. I. Cho, “Reduced Mitophagy in the Cochlea of Aged C57BL/6J Mice,” Experimental Gerontology 137 (2020): 110946.
- 96X. Wang and X. J. Chen, “A Cytosolic Network Suppressing Mitochondria-Mediated Proteostatic Stress and Cell Death,” Nature 524, no. 7566 (2015): 481–484.
- 97T. König and H. M. McBride, “Mitochondrial-Derived Vesicles in Metabolism, Disease, and Aging,” Cell Metabolism 36, no. 1 (2024): 21–35.
- 98A. Picca, F. Guerra, R. Calvani, et al., “Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease,” Journal of Clinical Medicine 9, no. 5 (2020): 1440.
- 99X. Yan, B. Wang, Y. Hu, S. Wang, and X. Zhang, “Abnormal Mitochondrial Quality Control in Neurodegenerative Diseases,” Frontiers in Cellular Neuroscience 14 (2020): 138.
- 100D. Matheoud, A. Sugiura, A. Bellemare-Pelletier, et al., “Parkinson's Disease-Related Proteins PINK1 and Parkin Repress Mitochondrial Antigen Presentation,” Cell 166, no. 2 (2016): 314–327.
- 101B. R. Alevriadou, A. Patel, M. Noble, et al., “Molecular Nature and Physiological Role of the Mitochondrial Calcium Uniporter Channel,” American Journal of Physiology—Cell Physiology 320, no. 4 (2021): C465–C482.
- 102I. de Ridder, M. Kerkhofs, F. O. Lemos, J. Loncke, G. Bultynck, and J. B. Parys, “The ER–Mitochondria Interface, Where Ca(2+) and Cell Death Meet,” Cell Calcium 112 (2023): 102743.
- 103M. Yuan, M. Gong, J. He, et al., “IP3R1/GRP75/VDAC1 Complex Mediates Endoplasmic Reticulum Stress–Mitochondrial Oxidative Stress in Diabetic Atrial Remodeling,” Redox Biology 52 (2022): 102289.
- 104K. Ooi, L. Hu, Y. Feng, et al., “Sigma-1 Receptor Activation Suppresses Microglia M1 Polarization via Regulating Endoplasmic Reticulum–Mitochondria Contact and Mitochondrial Functions in Stress-Induced Hypertension Rats,” Molecular Neurobiology 58, no. 12 (2021): 6625–6646.
- 105B. Honrath, I. Metz, N. Bendridi, J. Rieusset, C. Culmsee, and A. M. Dolga, “Glucose-Regulated Protein 75 Determines ER–Mitochondrial Coupling and Sensitivity to Oxidative Stress in Neuronal Cells,” Cell Death Discovery 3 (2017): 17076.
- 106T. Jiang, N. Ruan, P. Luo, et al., “Modulation of ER–Mitochondria Tethering Complex VAPB-PTPIP51: Novel Therapeutic Targets for Aging-Associated Diseases,” Ageing Research Reviews 98 (2024): 102320.
- 107O. M. de Brito and L. Scorrano, “Mitofusin 2 Tethers Endoplasmic Reticulum to Mitochondria,” Nature 456, no. 7222 (2008): 605–610.
- 108B. Schreiner, L. Hedskog, B. Wiehager, and M. Ankarcrona, “Amyloid-β Peptides Are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes,” Journal of Alzheimer's Disease 43, no. 2 (2014): 369–374.
10.3233/JAD-132543 Google Scholar
- 109K. H. Cheung, D. Shineman, M. Müller, et al., “Mechanism of Ca2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP3 Receptor Channel Gating,” Neuron 58, no. 6 (2008): 871–883.
- 110C. Supnet, J. Grant, H. Kong, D. Westaway, and M. Mayne, “Amyloid-β-(1-42) Increases Ryanodine Receptor-3 Expression and Function in Neurons of TgCRND8 Mice,” Journal of Biological Chemistry 281, no. 50 (2006): 38440–38447.
- 111J. More, N. Galusso, P. Veloso, et al., “N-Acetylcysteine Prevents the Spatial Memory Deficits and the Redox-Dependent RyR2 Decrease Displayed by an Alzheimer's Disease Rat Model,” Frontiers in Aging Neuroscience 10 (2018): 399.
- 112R. Stoica, K. J. De Vos, S. Paillusson, et al., “ER–the VAPB-PTPIP51 interactionInteraction regulates Mitochondria Associations and Are Disrupted by ALS/FTD-Associated TDP-43,” Nature Communications 5 (2014): 3996.
- 113P. Gomez-Suaga, G. M. Mórotz, A. Markovinovic, et al., “Disruption of ER–Mitochondria Tethering and Signalling in C9orf72-associated Amyotrophic Lateral Sclerosis and Frontotemporal Dementia,” Aging Cell 21, no. 2 (2022): e13549.
- 114F. Pilotto, A. Schmitz, N. Maharjan, et al., “PolyGA Targets the ER Stress-Adaptive Response by Impairing GRP75 Function at the MAM in C9ORF72-ALS/FTD,” Acta Neuropathologica 144, no. 5 (2022): 939–966.
- 115L. S. Jouaville, P. Pinton, C. Bastianutto, G. A. Rutter, and R. Rizzuto, “Regulation of Mitochondrial ATP Synthesis by Calcium: Evidence for a Long-Term Metabolic Priming,” Proceedings of the National Academy of Sciences 96, no. 24 (1999): 13807–13812.
- 116M. Carraro and P. Bernardi, “The Mitochondrial Permeability Transition Pore in Ca(2+) Homeostasis,” Cell Calcium 111 (2023): 102719.
- 117D. Poburko, J. Santo-Domingo, and N. Demaurex, “Dynamic Regulation of the Mitochondrial Proton Gradient During Cytosolic Calcium Elevations,” Journal of Biological Chemistry 286, no. 13 (2011): 11672–11684.
- 118C. Batandier, X. Leverve, and E. Fontaine, “Opening of the Mitochondrial Permeability Transition Pore Induces Reactive Oxygen Species Production at the Level of the Respiratory Chain Complex I,” Journal of Biological Chemistry 279, no. 17 (2004): 17197–17204.
- 119F. Korobova, V. Ramabhadran, and H. N. Higgs, “An Actin-Dependent Step in Mitochondrial Fission Mediated by the ER-Associated Formin INF2,” Science 339, no. 6118 (2013): 464–467.
- 120F. Korobova, T. J. Gauvin, and H. N. Higgs, “A Role for Myosin II in Mammalian Mitochondrial Fission,” Current Biology 24, no. 4 (2014): 409–414.
- 121R. Chakrabarti, W. K. Ji, R. V. Stan, J. de Juan Sanz, T. A. Ryan, and H. N. Higgs, “INF2-mediated Actin Polymerization at the ER Stimulates Mitochondrial Calcium Uptake, Inner Membrane Constriction, and Division,” Journal of Cell Biology 217, no. 1 (2018): 251–268.
- 122B. Cho, H. M. Cho, Y. Jo, et al., “Constriction of the Mitochondrial Inner Compartment Is a Priming Event for Mitochondrial Division,” Nature Communications 8 (2017): 15754.
- 123A. G. Erustes, M. D'Eletto, G. C. Guarache, et al., “Overexpression of α-synuclein Inhibits Mitochondrial Ca(2+) Trafficking Between the Endoplasmic Reticulum and Mitochondria Through MAMs by Altering the GRP75-IP3R Interaction,” Journal of Neuroscience Research 99, no. 11 (2021): 2932–2947.
- 124A. R. Thiam and E. Ikonen, “Lipid Droplet Nucleation,” Trends in Cell Biology 31, no. 2 (2021): 108–118.
- 125J. A. Olzmann and P. Carvalho, “Dynamics and Functions of Lipid Droplets,” Nature Reviews Molecular Cell Biology 20, no. 3 (2019): 137–155.
- 126M. Pu, W. Zheng, H. Zhang, et al., “ORP8 Acts as a Lipophagy Receptor to Mediate Lipid Droplet Turnover,” Protein & Cell 14, no. 9 (2023): 653–667.
- 127H. Wang, M. Becuwe, B. E. Housden, et al., “Seipin Is Required for Converting Nascent to Mature Lipid Droplets,” eLife 5 (2016): e16582.
- 128Z. Hong, J. Adlakha, N. Wan, et al., “Mitoguardin-2-Mediated Lipid Transfer Preserves Mitochondrial Morphology and Lipid Droplet Formation,” Journal of Cell Biology 221, no. 12 (2022): e202207022.
- 129Y. Zhang, X. Liu, J. Bai, et al., “Mitoguardin Regulates Mitochondrial Fusion Through MitoPLD and Is Required for Neuronal Homeostasis,” Molecular Cell 61, no. 1 (2016): 111–124.
- 130C. A. C. Freyre, P. C. Rauher, C. S. Ejsing, and R. W. Klemm, “MIGA2 Links Mitochondria, the ER, and Lipid Droplets and Promotes De Novo Lipogenesis in Adipocytes,” Molecular Cell 76, no. 5 (2019): 811–825.e14.
- 131V. F. Monteiro-Cardoso, L. Rochin, A. Arora, et al., “ORP5/8 and MIB/MICOS Link ER–Mitochondria and Intra-Mitochondrial Contacts for Non-Vesicular Transport of Phosphatidylserine,” Cell Reports 40, no. 12 (2022): 111364.
- 132V. Guyard, V. F. Monteiro-Cardoso, M. Omrane, et al., “ORP5 and ORP8 Orchestrate Lipid Droplet Biogenesis and Maintenance at ER–Mitochondria Contact Sites,” Journal of Cell Biology 221, no. 9 (2022): e202112107.
- 133Y. Combot, V. T. Salo, G. Chadeuf, et al., “Seipin Localizes at Endoplasmic–Reticulum–Mitochondria Contact Sites to Control Mitochondrial Calcium Import and Metabolism in Adipocytes,” Cell Reports 38, no. 2 (2022): 110213.
- 134A. P. Bailey, G. Koster, C. Guillermier, et al., “Antioxidant Role for Lipid Droplets in a Stem Cell Niche of Drosophila,” Cell 163, no. 2 (2015): 340–353.
- 135K. Palikaras, M. Mari, C. Ploumi, A. Princz, G. Filippidis, and N. Tavernarakis, “Age-Dependent Nuclear Lipid Droplet Deposition Is a Cellular Hallmark of Aging in Caenorhabditis elegans,” Aging Cell 22, no. 4 (2023): e13788.
- 136C. Franceschi, P. Garagnani, P. Parini, C. Giuliani, and A. Santoro, “Inflammaging: A New Immune-Metabolic Viewpoint for Age-Related Diseases,” Nature Reviews Endocrinology 14, no. 10 (2018): 576–590.
- 137T. J. Montine, C. H. Phelps, T. G. Beach, et al., “National Institute on Aging-Alzheimer's Association Guidelines for the Neuropathologic Assessment of Alzheimer's Disease: A Practical Approach,” Acta Neuropathologica 123, no. 1 (2012): 1–11.
- 138M. M. Klemmensen, S. H. Borrowman, C. Pearce, B. Pyles, and B. Chandra, “Mitochondrial Dysfunction in Neurodegenerative Disorders,” Neurotherapeutics 21, no. 1 (2024): e00292.
- 139R. H. Swerdlow, “Mitochondria and Mitochondrial Cascades in Alzheimer's Disease,” Journal of Alzheimer's Disease 62, no. 3 (2018): 1403–1416.
- 140R. Manjula, K. Anuja, and F. J. Alcain, “SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases,” Frontiers in Pharmacology 11 (2020): 585821.
- 141D. Y. Xia, X. Huang, C. F. Bi, L. L. Mao, L. J. Peng, and H. R. Qian, “PGC-1α or FNDC5 Is Involved in Modulating the Effects of Aβ(1-42) Oligomers on Suppressing the Expression of BDNF, a Beneficial Factor for Inhibiting Neuronal Apoptosis, Aβ Deposition and Cognitive Decline of APP/PS1 Tg Mice,” Frontiers in Aging Neuroscience 9 (2017): 65.
- 142H. R. Zimmermann, W. Yang, N. P. Kasica, et al., “Brain-Specific Repression of AMPKα1 Alleviates Pathophysiology in Alzheimer's Model Mice,” Journal of Clinical Investigation 130, no. 7 (2020): 3511–3527.
- 143P. H. Reddy and D. M. Oliver, “Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer's Disease,” Cells 8, no. 5 (2019): 488.
- 144J. Yan, X. H. Liu, M. Z. Han, et al., “Blockage of GSK3β-Mediated Drp1 Phosphorylation Provides Neuroprotection in Neuronal and Mouse Models of Alzheimer's Disease,” Neurobiology of Aging 36, no. 1 (2015): 211–227.
- 145J. Qu, T. Nakamura, G. Cao, E. A. Holland, S. R. McKercher, and S. A. Lipton, “S-Nitrosylation Activates Cdk5 and Contributes to Synaptic Spine Loss Induced by β-Amyloid Peptide,” Proceedings of the National Academy of Sciences 108, no. 34 (2011): 14330–14335.
- 146X. Guo, H. Sesaki, and X. Qi, “Drp1 Stabilizes p53 on the Mitochondria to Trigger Necrosis under Oxidative Stress Conditions In Vitro and In Vivo,” Biochemical Journal 461, no. 1 (2014): 137–146.
- 147J.-X. Wang, J.-Q. Jiao, Q. Li, et al., “miR-499 Regulates Mitochondrial Dynamics by Targeting Calcineurin and Dynamin-Related Protein-1,” Nature Medicine 17, no. 1 (2011): 71–78.
- 148M. Manczak, R. Kandimalla, D. Fry, H. Sesaki, and P. H. Reddy, “Protective Effects of Reduced Dynamin-Related Protein 1 Against Amyloid Beta-Induced Mitochondrial Dysfunction and Synaptic Damage in Alzheimer's Disease,” Human Molecular Genetics 25, no. 23 (2016): ddw330.
- 149K. N. Green, J. S. Steffan, H. Martinez-Coria, et al., “Nicotinamide Restores Cognition in Alzheimer's Disease Transgenic Mice via a Mechanism Involving Sirtuin Inhibition and Selective Reduction of Thr231-Phosphotau,” Journal of Neuroscience 28, no. 45 (2008): 11500–11510.
- 150D. Liu, M. Pitta, H. Jiang, et al., “Nicotinamide Forestalls Pathology and Cognitive Decline in Alzheimer Mice: Evidence for Improved Neuronal Bioenergetics and Autophagy Procession,” Neurobiology of Aging 34, no. 6 (2013): 1564–1580.
- 151H. Gutzmann and D. Hadler, Sustained Efficacy and Safety of Idebenone in the Treatment of Alzheimer's Disease: Update on a 2-Year Double-Blind Multicentre Study (Springer Vienna, 1998), 301–310.
- 152H. Lee, J. H. Park, and H. S. Hoe, “Idebenone Regulates Aβ and LPS-Induced Neurogliosis and Cognitive Function Through Inhibition of NLRP3 Inflammasome/IL-1β Axis Activation,” Frontiers in Immunology 13 (2022): 749336.
- 153L. Morató, J. Galino, M. Ruiz, et al., “Pioglitazone Halts Axonal Degeneration in a Mouse Model of X-Linked Adrenoleukodystrophy,” Brain 136, no. Pt 8 (2013): 2432–2443.
- 154A. Adlimoghaddam, G. G. Odero, G. Glazner, R. S. Turner, and B. C. Albensi, “Nilotinib Improves Bioenergetic Profiling in Brain Astroglia in the 3xTg Mouse Model of Alzheimer's Disease,” Aging and Disease 12, no. 2 (2021): 441–465.
- 155J. C. Komen and D. R. Thorburn, “Turn Up the Power—Pharmacological Activation of Mitochondrial Biogenesis in Mouse Models,” British Journal of Pharmacology 171, no. 8 (2014): 1818–1836.
- 156K. W. Zeng, J. K. Wang, L. C. Wang, et al., “Small Molecule Induces Mitochondrial Fusion for Neuroprotection via Targeting CK2 Without Affecting Its Conventional Kinase Activity,” Signal Transduction and Targeted Therapy 6, no. 1 (2021): 71.
- 157D. S. Jo, D. W. Shin, S. J. Park, et al., “Attenuation of Aβ Toxicity by Promotion of Mitochondrial Fusion in Neuroblastoma Cells by Liquiritigenin,” Archives of Pharmacal Research 39, no. 8 (2016): 1137–1143.
- 158B. Chhunchha, E. Kubo, R. R. Krueger, and D. P. Singh, “Hydralazine Revives Cellular and Ocular Lens Health-Span by Ameliorating the Aging and Oxidative-Dependent Loss of the Nrf2-Activated Cellular Stress Response,” Antioxidants 12, no. 1 (2023): 140.
- 159M. Maheshwari, J. K. Roberts, B. Desutter, et al., “Hydralazine Modifies Aβ Fibril Formation and Prevents Modification by Lipids in vitro,” Biochemistry 49, no. 49 (2010): 10371–10380.
- 160K. M. Wright, M. Bollen, J. David, et al., “Pharmacokinetics and Pharmacodynamics of Key Components of a Standardized Centella asiatica Product in Cognitively Impaired Older Adults: A Phase 1, Double-Blind, Randomized Clinical Trial,” Antioxidants 11, no. 2 (2022): 215.
- 161N. Xie, C. Wang, Y. Lian, C. Wu, H. Zhang, and Q. Zhang, “Inhibition of Mitochondrial Fission Attenuates Aβ-Induced Microglia Apoptosis,” Neuroscience 256 (2014): 36–42.
- 162C. Xie, X. X. Zhuang, Z. Niu, et al., “Amelioration of Alzheimer's Disease Pathology by Mitophagy Inducers Identified via Machine Learning and a Cross-Species Workflow,” Nature Biomedical Engineering 6, no. 1 (2022): 76–93.
- 163L. F. Lin, Y. T. Jhao, C. H. Chiu, et al., “Bezafibrate Exerts Neuroprotective Effects in a Rat Model of Sporadic Alzheimer's Disease,” Pharmaceuticals 15, no. 2 (2022): 109.
- 164L. Zhu, F. Lu, X. Zhang, S. Liu, and P. Mu, “SIRT1 Is Involved in the Neuroprotection of Pterostilbene Against Amyloid β 25-35-Induced Cognitive Deficits in Mice,” Frontiers in Pharmacology 13 (2022): 877098.
- 165D. Guerrieri and H. van Praag, “Exercise-Mimetic AICAR Transiently Benefits Brain Function,” Oncotarget 6, no. 21 (2015): 18293–18313.
- 166H. Qiu and X. Liu, “Echinacoside Improves Cognitive Impairment by Inhibiting Aβ Deposition Through the PI3K/AKT/Nrf2/PPARγ Signaling Pathways in APP/PS1 Mice,” Molecular Neurobiology 59, no. 8 (2022): 4987–4999.
- 167A. F. Batista, T. Rody, L. Forny-Germano, et al., “Interleukin-1β Mediates Alterations in Mitochondrial Fusion/Fission Proteins and Memory Impairment Induced by Amyloid-β Oligomers,” Journal of Neuroinflammation 18, no. 1 (2021): 54.
- 168Y. Wang, J. Zou, Y. Wang, et al., “Hydralazine Inhibits Neuroinflammation and Oxidative Stress in APP/PS1 Mice via TLR4/NF-κB and Nrf2 Pathways,” Neuropharmacology 240 (2023): 109706.
- 169H. Fujimori, T. Ohba, M. Mikami, et al., “The Protective Effect of Centella asiatica and Its Constituent, Araliadiol on Neuronal Cell Damage and Cognitive Impairment,” Journal of Pharmacological Sciences 148, no. 1 (2022): 162–171.
- 170Z. Chen, D. Zhao, M. Cheng, et al., “Female-Sensitive Multifunctional Phytoestrogen Nanotherapeutics for Tailored Management of Postmenopausal Alzheimer's Disease,” Nano Today 54 (2024): 102119.
- 171O. B. Tysnes and A. Storstein, “Epidemiology of Parkinson's Disease,” Journal of Neural Transmission 124, no. 8 (2017): 901–905.
- 172D. K. Simon, C. M. Tanner, and P. Brundin, “Parkinson Disease Epidemiology, Pathology, Genetics, and Pathophysiology,” Clinics in Geriatric Medicine 36, no. 1 (2020): 1–12.
- 173J. Blesa, I. Trigo-Damas, A. Quiroga-Varela, and V. R. Jackson-Lewis, “Oxidative Stress and Parkinson's Disease,” Frontiers in Neuroanatomy 9 (2015): 91.
- 174V. Dias, E. Junn, and M. M. Mouradian, “The Role of Oxidative Stress in Parkinson's Disease,” Journal of Parkinson's Disease 3, no. 4 (2013): 461–491.
- 175B. G. Trist, D. J. Hare, and K. L. Double, “Oxidative Stress in the Aging Substantia Nigra and the Etiology of Parkinson's Disease,” Aging Cell 18, no. 6 (2019): e13031.
- 176A. L. Mahul-Mellier, J. Burtscher, N. Maharjan, et al., “The Process of Lewy Body Formation, Rather Than Simply α-synuclein Fibrillization, Is One of the Major Drivers of Neurodegeneration,” Proceedings of the National Academy of Sciences 117, no. 9 (2020): 4971–4982.
- 177P. Calabresi, A. Mechelli, G. Natale, L. Volpicelli-Daley, G. Di Lazzaro, and V. Ghiglieri, “Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies: From Overt Neurodegeneration Back to Early Synaptic Dysfunction,” Cell Death & Disease 14, no. 3 (2023): 176.
- 178W. Chen, H. Zhao, and Y. Li, “Mitochondrial Dynamics in Health and Disease: Mechanisms and Potential Targets,” Signal Transduction and Targeted Therapy 8, no. 1 (2023): 333.
- 179Z. Li, K. I. Okamoto, Y. Hayashi, and M. Sheng, “The Importance of Dendritic Mitochondria in the Morphogenesis and Plasticity of Spines and Synapses,” Cell 119, no. 6 (2004): 873–887.
- 180A. Picca, F. Guerra, R. Calvani, et al., “Mitochondrial Signatures in Circulating Extracellular Vesicles of Older Adults With Parkinson's Disease: Results From the Exosomes in Parkinson's Disease (EXPAND) Study,” Journal of Clinical Medicine 9, no. 2 (2020): 504.
- 181D. Grimes, M. Fitzpatrick, J. Gordon, et al., “Canadian Guideline for Parkinson Disease,” Canadian Medical Association Journal 191, no. 36 (2019): E989–E1004.
- 182H. E. Moon and S. H. Paek, “Mitochondrial Dysfunction in Parkinson's Disease,” Experimental Neurobiology 24, no. 2 (2015): 103–116.
- 183V. S. Burchell, S. Gandhi, E. Deas, N. W. Wood, A. Y. Abramov, and H. Plun-Favreau, “Targeting Mitochondrial Dysfunction in Neurodegenerative Disease: Part I,” Expert Opinion on Therapeutic Targets 14, no. 4 (2010): 369–385.
- 184D. A. Monti, G. Zabrecky, D. Kremens, et al., “N-Acetyl Cysteine Is Associated With Dopaminergic Improvement in Parkinson's Disease,” Clinical Pharmacology & Therapeutics 106, no. 4 (2019): 884–890.
- 185H. Mortiboys, R. Furmston, G. Bronstad, J. Aasly, C. Elliott, and O. Bandmann, “UDCA Exerts Beneficial Effect on Mitochondrial Dysfunction in LRRK2(G2019S) Carriers and in Vivo,” Neurology 85, no. 10 (2015): 846–852.
- 186H. Mortiboys, J. Aasly, and O. Bandmann, “Ursocholanic Acid Rescues Mitochondrial Function in Common Forms of Familial Parkinson's Disease,” Brain 136, no. Pt 10 (2013): 3038–3050.
- 187S. Lautrup, D. A. Sinclair, M. P. Mattson, and E. F. Fang, “NAD(+) in Brain Aging and Neurodegenerative Disorders,” Cell Metabolism 30, no. 4 (2019): 630–655.
- 188D. Conze, C. Brenner, and C. L. Kruger, “Safety and Metabolism of Long-Term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-Controlled Clinical Trial of Healthy Overweight Adults,” Scientific Reports 9, no. 1 (2019): 9772.
- 189 NINDS Exploratory Trials in Parkinson Disease (NET-PD) FS-ZONE Investigators and T. Simuni, "Pioglitazone in Early Parkinson's Disease: A Phase 2, Multicentre, Double-Blind, Randomised Trial,” Lancet Neurology 14, no. 8 (2015): 795–803.
- 190B. Liss and J. Striessnig, “The Potential of L-Type Calcium Channels as a Drug Target for Neuroprotective Therapy in Parkinson's Disease,” Annual Review of Pharmacology and Toxicology 59 (2019): 263–289.
- 191C. S. Venuto, L. Yang, M. Javidnia, D. Oakes, D. James Surmeier, and T. Simuni, “Isradipine Plasma Pharmacokinetics and Exposure-Response in Early Parkinson's Disease,” Annals of Clinical and Translational Neurology 8, no. 3 (2021): 603–612.
- 192N. T. Hertz, A. Berthet, M. L. Sos, et al., “A Neo-Substrate That Amplifies Catalytic Activity of Parkinson's-Disease-Related Kinase PINK1,” Cell 154, no. 4 (2013): 737–747.
- 193N. Singh, M. A. Savanur, S. Srivastava, P. D'Silva, and G. Mugesh, “A Redox Modulatory Mn(3) O(4) Nanozyme With Multi-Enzyme Activity Provides Efficient Cytoprotection to Human Cells in a Parkinson's Disease Model,” Angewandte Chemie International Edition 56, no. 45 (2017): 14267–14271.
- 194E. G. Heckert, A. S. Karakoti, S. Seal, and W. T. Self, “The Role of Cerium Redox State in the SOD Mimetic Activity of Nanoceria,” Biomaterials 29, no. 18 (2008): 2705–2709.
- 195C. Huang, W. Ma, Q. Luo, et al., “Iron Overload Resulting From the Chronic Oral Administration of Ferric Citrate Induces Parkinsonism Phenotypes in Middle-Aged Mice,” Aging 11, no. 21 (2019): 9846–9861.
- 196J. Prasuhn, M. Göttlich, F. Gerkan, et al., “Relationship Between Brain Iron Deposition and Mitochondrial Dysfunction in Idiopathic Parkinson's Disease,” Molecular Medicine 28, no. 1 (2022): 28.
- 197D. G. Lee, M. K. Kam, S. R. Lee, H. J. Lee, and D. S. Lee, “Peroxiredoxin 5 Deficiency Exacerbates Iron Overload-Induced Neuronal Death via ER-Mediated Mitochondrial Fission in Mouse Hippocampus,” Cell Death & Disease 11, no. 3 (2020): 204.
- 198D. G. Lee, J. Park, H. S. Lee, S. R. Lee, and D. S. Lee, “Iron Overload-Induced Calcium Signals Modulate Mitochondrial Fragmentation in HT-22 Hippocampal Neuron Cells,” Toxicology 365 (2016): 17–24.
- 199C. Guo, L. J. Hao, Z. H. Yang, et al., “Deferoxamine-Mediated Up-Regulation of HIF-1α Prevents Dopaminergic Neuronal Death via the Activation of MAPK Family Proteins in MPTP-Treated Mice,” Experimental Neurology 280 (2016): 13–23.
- 200D. Kaur, F. Yantiri, S. Rajagopalan, et al., “Genetic or Pharmacological Iron Chelation Prevents MPTP-Induced Neurotoxicity in vivo,” Neuron 37, no. 6 (2003): 899–909.
- 201D. B. Shachar, N. Kahana, V. Kampel, A. Warshawsky, and M. B. H. Youdim, “Neuroprotection by a Novel Brain Permeable Iron Chelator, VK-28, Against 6-Hydroxydopamine Lession in Rats,” Neuropharmacology 46, no. 2 (2004): 254–263.
- 202L. Millichap, N. Turton, E. Damiani, et al., “The Effect of Neuronal CoQ(10) Deficiency and Mitochondrial Dysfunction on a Rotenone-Induced Neuronal Cell Model of Parkinson's Disease,” International Journal of Molecular Sciences 25, no. 12 (2024): 6622.
- 203R. Caridade-Silva, B. Araújo, J. Martins-Macedo, and F. G. Teixeira, “N-Acetylcysteine Treatment May Compensate Motor Impairments Through Dopaminergic Transmission Modulation in a Striatal 6-Hydroxydopamine Parkinson's Disease Rat Model,” Antioxidants 12, no. 6 (2023): 1257.
- 204L. D. Coles, P. J. Tuite, G. Öz, et al., “Repeated-Dose Oral N-Acetylcysteine in Parkinson's Disease: Pharmacokinetics and Effect on Brain Glutathione and Oxidative Stress,” Journal of Clinical Pharmacology 58, no. 2 (2018): 158–167.
- 205M. J. Holmay, M. Terpstra, L. D. Coles, et al., “N-Acetylcysteine Boosts Brain and Blood Glutathione in Gaucher and Parkinson Diseases,” Clinical Neuropharmacology 36, no. 4 (2013): 103–106.
- 206H. Qi, D. Shen, C. Jiang, H. Wang, and M. Chang, “Ursodeoxycholic Acid Protects Dopaminergic Neurons From Oxidative Stress via Regulating Mitochondrial Function, Autophagy, and Apoptosis in MPTP/MPP(+)-Induced Parkinson's Disease,” Neuroscience Letters 741 (2021): 135493.
- 207T. Payne, M. Appleby, E. Buckley, et al., “A Double-Blind, Randomized, Placebo-Controlled Trial of Ursodeoxycholic Acid (UDCA) in Parkinson's Disease,” Movement Disorders 38, no. 8 (2023): 1493–1502.
- 208B. Brakedal, C. Dölle, F. Riemer, et al., “The NADPARK Study: A Randomized Phase I Trial of Nicotinamide Riboside Supplementation in Parkinson's Disease,” Cell Metabolism 34, no. 3 (2022): 396–407.e6.
- 209G. Turconi, F. Alam, T. SenGupta, et al., “Nicotinamide Riboside First Alleviates Symptoms but Later Downregulates Dopamine Metabolism in Proteasome Inhibition Mouse Model of Parkinson's Disease,” Heliyon 10, no. 14 (2024): e34355.
- 210K. Kieburtz, B. C. Tilley, J. J. Elm, et al., “Effect of Creatine Monohydrate on Clinical Progression in Patients With Parkinson Disease: A Randomized Clinical Trial,” Journal of the American Medical Association (Chicago, IL) 313, no. 6 (2015): 584–593.
- 211C. J. Jagaraj, S. Shadfar, S. A. Kashani, S. Saravanabavan, F. Farzana, and J. D. Atkin, “Molecular Hallmarks of Ageing in Amyotrophic Lateral Sclerosis,” Cellular and Molecular Life Sciences 81, no. 1 (2024): 111.
- 212S. Sasaki and M. Iwata, “Mitochondrial Alterations in the Spinal Cord of Patients With Sporadic Amyotrophic Lateral Sclerosis,” Journal of Neuropathology and Experimental Neurology 66, no. 1 (2007): 10–16.
- 213E. C. Genin, B. Madji Hounoum, S. Bannwarth, et al., “Mitochondrial Defect in Muscle Precedes Neuromuscular Junction Degeneration and Motor Neuron Death in CHCHD10(S59L/+) Mouse,” Acta Neuropathologica 138, no. 1 (2019): 123–145.
- 214T. Singh, Y. Jiao, L. M. Ferrando, et al., “Neuronal Mitochondrial Dysfunction in Sporadic Amyotrophic Lateral Sclerosis Is Developmentally Regulated,” Scientific Reports 11, no. 1 (2021): 18916.
- 215J. Magrané, C. Cortez, W. B. Gan, and G. Manfredi, “Abnormal Mitochondrial Transport and Morphology Are Common Pathological Denominators in SOD1 and TDP43 ALS Mouse Models,” Human Molecular Genetics 23, no. 6 (2014): 1413–1424.
- 216A. Singh, R. Kukreti, L. Saso, and S. Kukreti, “Oxidative Stress: A Key Modulator in Neurodegenerative Diseases,” Molecules 24, no. 8 (2019): 1583.
- 217S. Gandhi and A. Y. Abramov, “Mechanism of Oxidative Stress in Neurodegeneration,” Oxidative Medicine and Cellular Longevity 2012 (2012): 428010.
- 218E. C. Genin, M. Abou-Ali, and V. Paquis-Flucklinger, “Mitochondria, a Key Target in Amyotrophic Lateral Sclerosis Pathogenesis,” Genes 14, no. 11 (2023): 1981.
- 219P. Van Damme, A. Al-Chalabi, P. M. Andersen, et al., “European Academy of Neurology (EAN) Guideline on the Management of Amyotrophic Lateral Sclerosis in Collaboration With European Reference Network for Neuromuscular Diseases (ERN EURO-NMD),” European Journal of Neurology 31, no. 6 (2024): e16264.
- 220M. K. Jaiswal, “Riluzole and Edaravone: A Tale of Two Amyotrophic Lateral Sclerosis Drugs,” Medicinal Research Reviews 39, no. 2 (2019): 733–748.
- 221Y. Deng, Z.-F. Xu, W. Liu, B. Xu, H.-B. Yang, and Y.-G. Wei, “Riluzole-Triggered GSH Synthesis via Activation of Glutamate Transporters to Antagonize Methylmercury-Induced Oxidative Stress in Rat Cerebral Cortex,” Oxidative Medicine and Cellular Longevity 2012, no. 1 (2012): 534705.
- 222J. Y. Koh, D. K. Kim, J. Y. Hwang, Y. H. Kim, and J. H. Seo, “Antioxidative and Proapoptotic Effects of Riluzole on Cultured Cortical Neurons,” Journal of Neurochemistry 72, no. 2 (1999): 716–723.
- 223M. K. Jaiswal, “Riluzole But Not Melatonin Ameliorates Acute Motor Neuron Degeneration and Moderately Inhibits SOD1-Mediated Excitotoxicity Induced Disrupted Mitochondrial Ca(2+) Signaling in Amyotrophic Lateral Sclerosis,” Frontiers in Cellular Neuroscience 10 (2016): 295.
- 224S. Kapoor, “Neuroprotective Effects of Edaravone: Recent Insights,” Journal of the Neurological Sciences 331, no. 1–2 (2013): 177.
- 225J. D. Rothstein, “Edaravone: A New Drug Approved for ALS,” Cell 171, no. 4 (2017): 725.
- 226K. Valko and L. Ciesla, “Amyotrophic Lateral Sclerosis,” Progress in Medicinal Chemistry 58 (2019): 63–117.
- 227Q. Li, Z. Qiu, Y. Lu, et al., “Edaravone Protects Primary-Cultured Rat Cortical Neurons From Ketamine-Induced Apoptosis via Reducing Oxidative Stress and Activating PI3K/Akt Signal Pathway,” Molecular and Cellular Neuroscience 100 (2019): 103399.
- 228T. Watanabe, M. Tahara, and S. Todo, “The Novel Antioxidant Edaravone: From Bench to Bedside,” Cardiovascular Therapeutics 26, no. 2 (2008): 101–114.
- 229S. Paganoni, E. A. Macklin, S. Hendrix, et al., “Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis,” New England Journal of Medicine 383, no. 10 (2020): 919–930.
- 230J. A. Fels, J. Dash, K. Leslie, G. Manfredi, and H. Kawamata, “Effects of PB-TURSO on the Transcriptional and Metabolic Landscape of Sporadic ALS Fibroblasts,” Annals of Clinical and Translational Neurology 9, no. 10 (2022): 1551–1564.
- 231T. Meyer, P. Schumann, P. Weydt, et al., “Neurofilament Light-Chain Response During Therapy With Antisense Oligonucleotide Tofersen in SOD1-related ALS: Treatment Experience in Clinical Practice,” Muscle & Nerve 67, no. 6 (2023): 515–521.
- 232A. McCampbell, T. Cole, A. J. Wegener, et al., “Antisense Oligonucleotides Extend Survival and Reverse Decrement in Muscle Response in ALS Models,” Journal of Clinical Investigation 128, no. 8 (2018): 3558–3567.
- 233L. Packer, H. J. Tritschler, and K. Wessel, “Neuroprotection by the Metabolic Antioxidant α-Lipoic Acid,” Free Radical Biology and Medicine 22, no. 1–2 (1997): 359–378.
- 234R. Dafinca, P. Barbagallo, and K. Talbot, “The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS,” Frontiers in Cellular Neuroscience 15 (2021): 653688.
- 235K. N. Alavian, S. I. Dworetzky, L. Bonanni, et al., “Effects of Dexpramipexole on Brain Mitochondrial Conductances and Cellular Bioenergetic Efficiency,” Brain Research 1446 (2012): 1–11.
- 236F. Fornai, P. Longone, L. Cafaro, et al., “Lithium Delays Progression of Amyotrophic Lateral Sclerosis,” Proceedings of the National Academy of Sciences 105, no. 6 (2008): 2052–2057.
- 237S. Waibel, A. Reuter, S. Malessa, E. Blaugrund, and A. Ludolph, “Rasagiline Alone and in Combination With Riluzole Prolongs Survival in an ALS Mouse Model,” Journal of Neurology 251, no. 9 (2004): 1080–1084.
- 238N. Bernard-Marissal, C. Sunyach, T. Marissal, C. Raoul, and B. Pettmann, “Calreticulin Levels Determine Onset of Early Muscle Denervation by Fast Motoneurons of ALS Model Mice,” Neurobiology of Disease 73 (2015): 130–136.
- 239D. H. W. Lau, N. Hartopp, N. J. Welsh, et al., “Disruption of ER–Mitochondria Signalling in Fronto-Temporal Dementia and Related Amyotrophic Lateral Sclerosis,” Cell Death & Disease 9, no. 3 (2018): 327.
- 240S. Paganoni, S. Hendrix, S. P. Dickson, et al., “Long-Term Survival of Participants in the CENTAUR Trial of Sodium Phenylbutyrate–Taurursodiol in Amyotrophic Lateral Sclerosis,” Muscle & Nerve 63, no. 1 (2021): 31–39.
- 241K. Thakor, S. Naud, D. Howard, R. Tandan, and W. Waheed, “Effect of Riluzole on Weight in Short-Term and Long-Term Survivors of Amyotrophic Lateral Sclerosis,” Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 22, no. 5–6 (2021): 360–367.
- 242N. J. Thakore, B. R. Lapin, H. Mitsumoto, and Pooled Resource Open-Access ALS Clinical Trials Consortium, “Early Initiation of Riluzole May Improve Absolute Survival in Amyotrophic Lateral Sclerosis,” Muscle & Nerve 66, no. 6 (2022): 702–708.
- 243H. Houzen, T. Kano, K. Horiuchi, M. Wakita, A. Nagai, and I. Yabe, “Improved Long-Term Survival With Edaravone Therapy in Patients With Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan,” Pharmaceuticals 14, no. 8 (2021): 705.
- 244A. Kakimoto, M. Ishizaki, H. Ueyama, Y. Maeda, and M. Ueda, “Renal Function in Amyotrophic Lateral Sclerosis Patients on Long-Term Treatment With Edaravone,” Medicine 100, no. 21 (2021): e26127.
- 245T. Meyer, P. Schumann, P. Weydt, et al., “Clinical and Patient-Reported Outcomes and Neurofilament Response During Tofersen Treatment in SOD1-Related ALS—A Multicenter Observational Study Over 18 Months,” Muscle & Nerve 70, no. 3 (2024): 333–345.
- 246H. Khan, T. G. Singh, R. S. Dahiya, and M. M. Abdel-Daim, “α-Lipoic Acid, an Organosulfur Biomolecule a Novel Therapeutic Agent for Neurodegenerative Disorders: An Mechanistic Perspective,” Neurochemical Research 47, no. 7 (2022): 1853–1864.
- 247K. E. Morrison, S. Dhariwal, R. Hornabrook, et al, “Lithium in Patients With Amyotrophic Lateral Sclerosis (LiCALS): A Phase 3 Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial,” Lancet Neurology 12, no. 4 (2013): 339–345.
- 248J. Schuster, J. Dreyhaupt, K. Mönkemöller, et al., “In-Depth Analysis of Data From the RAS-ALS Study Reveals New Insights in Rasagiline Treatment for Amyotrophic Lateral Sclerosis,” European Journal of Neurology 31, no. 4 (2024): e16204.
- 249S. S. Virani, L. K. Newby, S. V. Arnold, et al., “2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines,” Circulation 148, no. 9 (2023): e9–e119.
- 250D. Zhu, H. F. Chung, A. J. Dobson, et al., “Age at Natural Menopause and Risk of Incident Cardiovascular Disease: A Pooled Analysis of Individual Patient Data,” Lancet Public Health 4, no. 11 (2019): e553–e564.
- 251V. Dam, N. C. Onland-Moret, S. Burgess, et al., “Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-Sample Mendelian Randomization,” Journal of Clinical Endocrinology & Metabolism 107, no. 7 (2022): e2952–e2961.
- 252A. V. Poznyak, E. A. Ivanova, I. A. Sobenin, S. F. Yet, and A. N. Orekhov, “The Role of Mitochondria in Cardiovascular Diseases,” Biology 9, no. 6 (2020): 137.
- 253M. Staiculescu, C. Foote, G. Meininger, and L. Martinez-Lemus, “The Role of Reactive Oxygen Species in Microvascular Remodeling,” International Journal of Molecular Sciences 15, no. 12 (2014): 23792–23835.
- 254I. Perrotta, E. Brunelli, A. Sciangula, et al., “iNOS Induction and PARP-1 Activation in Human Atherosclerotic Lesions: An Immunohistochemical and Ultrastructural Approach,” Cardiovascular Pathology 20, no. 4 (2011): 195–203.
- 255H. A. Cooper, S. Cicalese, K. J. Preston, et al., “Targeting Mitochondrial Fission as a Potential Therapeutic for Abdominal Aortic Aneurysm,” Cardiovascular Research 117, no. 3 (2021): 971–982.
- 256T. Fiorentino, A. Prioletta, P. Zuo, and F. Folli, “Hyperglycemia-Induced Oxidative Stress and Its Role in Diabetes Mellitus Related Cardiovascular Diseases,” Current Pharmaceutical Design 19, no. 32 (2013): 5695–5703.
- 257S. H. Park, S. Y. Lee, and S. A. Kim, “Mitochondrial DNA Methylation Is Higher in Acute Coronary Syndrome Than in Stable Coronary Artery Disease,” In Vivo 35, no. 1 (2021): 181–189.
- 258N. Botto, S. Berti, S. Manfredi, et al., “Detection of mtDNA With 4977 bp Deletion in Blood Cells and Atherosclerotic Lesions of Patients With Coronary Artery Disease,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 570, no. 1 (2005): 81–88.
- 259M. Corral-Debrinski, J. M. Shoffner, M. T. Lott, and D. C. Wallace, “Association of Mitochondrial DNA Damage With Aging and Coronary Atherosclerotic Heart Disease,” Mutation Research/DNAging 275, no. 3–6 (1992): 169–180.
- 260N. Torres, M. Guevara-Cruz, L. A. Velázquez-Villegas, and A. R. Tovar, “Nutrition and Atherosclerosis,” Archives of Medical Research 46, no. 5 (2015): 408–426.
- 261R. M. Parodi-Rullán, X. Chapa-Dubocq, P. J. Rullán, S. Jang, and S. Javadov, “High Sensitivity of SIRT3 Deficient Hearts to Ischemia-Reperfusion Is Associated With Mitochondrial Abnormalities,” Frontiers in Pharmacology 8 (2017): 275.
- 262A. E. Dikalova, H. A. Itani, R. R. Nazarewicz, et al., “Sirt3 Impairment and SOD2 Hyperacetylation in Vascular Oxidative Stress and Hypertension,” Circulation Research 121, no. 5 (2017): 564–574.
- 263H. Yamamoto, K. Morino, L. Mengistu, et al., “Amla Enhances Mitochondrial Spare Respiratory Capacity by Increasing Mitochondrial Biogenesis and Antioxidant Systems in a Murine Skeletal Muscle Cell Line,” Oxidative Medicine and Cellular Longevity 2016 (2016): 1735841.
- 264Z. Li, Q. Zhong, T. Yang, X. Xie, and M. Chen, “The Role of Profilin-1 in Endothelial Cell Injury Induced by Advanced Glycation End Products (AGEs),” Cardiovascular Diabetology 12 (2013): 141.
- 265G. R. Romeo and A. Kazlauskas, “Oxysterol and Diabetes Activate STAT3 and Control Endothelial Expression of Profilin-1 via OSBP1,” Journal of Biological Chemistry 283, no. 15 (2008): 9595–9605.
- 266P. S. Gurel, A. Mu, B. Guo, R. Shu, D. F. Mierke, and H. N. Higgs, “Assembly and Turnover of Short Actin Filaments by the Formin INF2 and Profilin,” Journal of Biological Chemistry 290, no. 37 (2015): 22494–22506.
- 267E. A. Bordt, P. Clerc, B. A. Roelofs, et al., “The Putative Drp1 Inhibitor mdivi-1 Is a Reversible Mitochondrial Complex I Inhibitor That Modulates Reactive Oxygen Species,” Developmental Cell 40, no. 6 (2017): 583–594.e6.
- 268A. V. Birk, S. Liu, Y. Soong, et al., “The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting With Cardiolipin,” Journal of the American Society of Nephrology 24, no. 8 (2013): 1250–1261.
- 269O. M. Duicu, R. Lighezan, A. Sturza, et al., “Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts,” Oxidative Medicine and Cellular Longevity 2016 (2016): 8470394.
- 270B. Mathew, G. Uçar, G. E. Mathew, et al., “Monoamine Oxidase Inhibitory Activity: Methyl- Versus Chlorochalcone Derivatives,” ChemMedChem 11, no. 24 (2016): 2649–2655.
- 271N. O. Zarmouh, S. S. Messeha, F. M. Elshami, and K. F. A. Soliman, “Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and -B Inhibitor,” Evidence-Based Complementary and Alternative Medicine 2016 (2016): 1423052.
- 272A. V. Lokhmatikov, N. Voskoboynikova, D. A. Cherepanov, et al., “Impact of Antioxidants on Cardiolipin Oxidation in Liposomes: Why Mitochondrial Cardiolipin Serves as an Apoptotic Signal?,” Oxidative Medicine and Cellular Longevity 2016 (2016): 8679469.
- 273S. Katsuki and J. Koga, “Mitochondrial Uncoupling: A Fine-Tuning Knob for Mitochondria-Targeting Therapeutics for Coronary Artery Disease,” Journal of Atherosclerosis and Thrombosis 29, no. 6 (2022): 811–813.
- 274S. Bellary, I. Kyrou, J. E. Brown, and C. J. Bailey, “Type 2 Diabetes Mellitus in Older Adults: Clinical Considerations and Management,” Nature Reviews Endocrinology 17, no. 9 (2021): 534–548.
- 275R. R. Kalyani, S. H. Golden, and W. T. Cefalu, “Diabetes and Aging: Unique Considerations and Goals of Care,” Diabetes Care 40, no. 4 (2017): 440–443.
- 276M. Anello, R. Lupi, D. Spampinato, et al., “Functional and Morphological Alterations of Mitochondria in Pancreatic Beta Cells From Type 2 Diabetic Patients,” Diabetologia 48, no. 2 (2005): 282–289.
- 277J. Fu, Q. Cui, B. Yang, et al., “The Impairment of Glucose-Stimulated Insulin Secretion in Pancreatic β-cells Caused by Prolonged Glucotoxicity and Lipotoxicity Is Associated With Elevated Adaptive Antioxidant Response,” Food and Chemical Toxicology 100 (2017): 161–167.
- 278C. Jimenez-Sánchez, T. Brun, and P. Maechler, “Mitochondrial Carriers Regulating Insulin Secretion Profiled in Human Islets Upon Metabolic Stress,” Biomolecules 10, no. 11 (2020): 1543.
- 279A. Deniaud, O. Sharaf el dein, E. Maillier, et al., “Endoplasmic Reticulum Stress Induces Calcium-Dependent Permeability Transition, Mitochondrial Outer Membrane Permeabilization and Apoptosis,” Oncogene 27, no. 3 (2008): 285–299.
- 280L. D. Ly, D. D. Ly, N. T. Nguyen, et al., “Mitochondrial Ca(2+) Uptake Relieves Palmitate-Induced Cytosolic Ca(2+) Overload in MIN6 Cells,” Molecules and Cells 43, no. 1 (2020): 66–75.
- 281L. M. Cree, S. K. Patel, A. Pyle, et al., “Age-Related Decline in Mitochondrial DNA Copy Number in Isolated Human Pancreatic Islets,” Diabetologia 51, no. 8 (2008): 1440–1443.
- 282D. L. Nile, A. E. Brown, M. A. Kumaheri, et al., “Age-Related Mitochondrial DNA Depletion and the Impact on Pancreatic Beta Cell Function,” PLoS One 9, no. 12 (2014): e115433.
- 283C. Koliaki, J. Szendroedi, K. Kaul, et al., “Adaptation of Hepatic Mitochondrial Function in Humans With Non-Alcoholic Fatty Liver Is Lost in Steatohepatitis,” Cell Metabolism 21, no. 5 (2015): 739–746.
- 284A. I. Schmid, J. Szendroedi, M. Chmelik, M. Krššák, E. Moser, and M. Roden, “Liver ATP Synthesis Is Lower and Relates to Insulin Sensitivity in Patients With Type 2 Diabetes,” Diabetes Care 34, no. 2 (2011): 448–453.
- 285J. Szendroedi, M. Chmelik, A. I. Schmid, et al., “Abnormal Hepatic Energy Homeostasis in Type 2 Diabetes,” Hepatology 50, no. 4 (2009): 1079–1086.
- 286M. Chattopadhyay, V. K. Khemka, G. Chatterjee, A. Ganguly, S. Mukhopadhyay, and S. Chakrabarti, “Enhanced ROS Production and Oxidative Damage in Subcutaneous White Adipose Tissue Mitochondria in Obese and Type 2 Diabetes Subjects,” Molecular and Cellular Biochemistry 399, no. 1–2 (2015): 95–103.
- 287E. Nilsson, P. A. Jansson, A. Perfilyev, et al., “Altered DNA Methylation and Differential Expression of Genes Influencing Metabolism and Inflammation in Adipose Tissue From Subjects With Type 2 Diabetes,” Diabetes 63, no. 9 (2014): 2962–2976.
- 288E. R. Dabkowski, W. A. Baseler, C. L. Williamson, et al., “Mitochondrial Dysfunction in the Type 2 Diabetic Heart Is Associated With Alterations in Spatially Distinct Mitochondrial Proteomes,” American Journal of Physiology—Heart and Circulatory Physiology 299, no. 2 (2010): H529–H540.
- 289J. A. Kanaley, S. R. Colberg, M. H. Corcoran, et al., “Exercise/Physical Activity in Individuals With Type 2 Diabetes: A Consensus Statement From the American College of Sports Medicine,” Medicine & Science in Sports & Exercise 54, no. 2 (2022): 353–368.
- 290J. P. Thyfault and A. Bergouignan, “Exercise and Metabolic Health: Beyond Skeletal Muscle,” Diabetologia 63, no. 8 (2020): 1464–1474.
- 291F. J. DiMenna and A. D. Arad, “Exercise as ‘Precision Medicine’ for Insulin Resistance and Its Progression to Type 2 Diabetes: A Research Review,” BMC Sports Science, Medicine & Rehabilitation 10 (2018): 21.
- 292N. Krako Jakovljevic, K. Pavlovic, A. Jotic, et al., “Targeting Mitochondria in Diabetes,” International Journal of Molecular Sciences 22, no. 12 (2021): 6642.
- 293Y. Dvoretskaya, V. Glanz, M. Gryaznova, M. Syromyatnikov, and V. Popov, “Mitochondrial Antioxidant SkQ1 has a Beneficial Effect in Experimental Diabetes as Based on the Analysis of Expression of microRNAs and mRNAs for the Oxidative Metabolism Regulators,” Antioxidants 10, no. 11 (2021): 1749.
- 294H. H. Szeto, “Mitochondria-Targeted Cytoprotective Peptides for Ischemia-Reperfusion Injury,” Antioxidants & Redox Signaling 10, no. 3 (2008): 601–620.
- 295M. Lagouge, C. Argmann, Z. Gerhart-Hines, et al., “Resveratrol Improves Mitochondrial Function and Protects Against Metabolic Disease by Activating SIRT1 and PGC-1α,” Cell 127, no. 6 (2006): 1109–1122.
- 296R. H. Choi, A. McConahay, M. B. Johnson, H. W. Jeong, and H. J. Koh, “Adipose Tissue-Specific Knockout of AMPKα1/α2 Results in Normal AICAR Tolerance and Glucose Metabolism,” Biochemical and Biophysical Research Communications 519, no. 3 (2019): 633–638.
- 297N. T. Broskey, C. Greggio, A. Boss, et al., “Skeletal Muscle Mitochondria in the Elderly: Effects of Physical Fitness and Exercise Training,” Journal of Clinical Endocrinology and Metabolism 99, no. 5 (2014): 1852–1861.
- 298Y. M. Song, Y. Lee, J. W. Kim, et al., “Metformin Alleviates Hepatosteatosis by Restoring SIRT1-Mediated Autophagy Induction via an AMP-Activated Protein Kinase-Independent Pathway,” Autophagy 11, no. 1 (2015): 46–59.
- 299A. Qaseem, A. J. Obley, T. Shamliyan, et al., “Newer Pharmacologic Treatments in Adults With Type 2 Diabetes: A Clinical Guideline From the American College of Physicians,” Annals of Internal Medicine 177, no. 5 (2024): 658–666.
- 300K. Park, H. Lim, J. Kim, et al., “Lysosomal Ca(2+)-Mediated TFEB Activation Modulates Mitophagy and Functional Adaptation of Pancreatic β-Cells to Metabolic Stress,” Nature Communications 13, no. 1 (2022): 1300.
- 301A. M. Toney, R. Fan, Y. Xian, V. Chaidez, A. E. Ramer-Tait, and S. Chung, “Urolithin A, a Gut Metabolite, Improves Insulin Sensitivity Through Augmentation of Mitochondrial Function and Biogenesis,” Obesity 27, no. 4 (2019): 612–620.
- 302I. Chareyron, S. Christen, S. Moco, et al., “Augmented Mitochondrial Energy Metabolism Is an Early Response to Chronic Glucose Stress in Human Pancreatic Beta Cells,” Diabetologia 63, no. 12 (2020): 2628–2640.
- 303H. T. Nguyen, C. Noriega Polo, A. Wiederkehr, C. B. Wollheim, and K. S. Park, “CDN1163, an Activator of Sarco/Endoplasmic Reticulum Ca(2+) ATPase, Up-Regulates Mitochondrial Functions and Protects Against Lipotoxicity in Pancreatic Β-Cells,” British Journal of Pharmacology 180, no. 21 (2023): 2762–2776.
- 304F. Bray, M. Laversanne, H. Sung, et al., “Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 74, no. 3 (2024): 229–263.
- 305O. Warburg, “On the Origin of Cancer Cells,” Science 123, no. 3191 (1956): 309–314.
- 306L. Sainero-Alcolado, J. Liaño-Pons, M. V. Ruiz-Pérez, and M. Arsenian-Henriksson, “Targeting Mitochondrial Metabolism for Precision Medicine in Cancer,” Cell Death & Differentiation 29, no. 7 (2022): 1304–1317.
- 307Z. Q. Zheng, Z. X. Li, J. L. Guan, et al., “Long Noncoding RNA TINCR-Mediated Regulation of Acetyl-CoA Metabolism Promotes Nasopharyngeal Carcinoma Progression and Chemoresistance,” Cancer Research 80, no. 23 (2020): 5174–5188.
- 308M. Dai, B. Yang, J. Chen, et al., “Nuclear-Translocation of ACLY Induced by Obesity-Related Factors Enhances Pyrimidine Metabolism Through Regulating Histone Acetylation in Endometrial Cancer,” Cancer Letters 513 (2021): 36–49.
- 309J. Miska and N. S. Chandel, “Targeting Fatty Acid Metabolism in Glioblastoma,” Journal of Clinical Investigation 133, no. 1 (2023): e163448.
- 310C. Zhang, X. Y. Wang, P. Zhang, et al., “Cancer-Derived Exosomal HSPC111 Promotes Colorectal Cancer Liver Metastasis by Reprogramming Lipid Metabolism in Cancer-Associated Fibroblasts,” Cell Death & Disease 13, no. 1 (2022): 57.
- 311Z. Yan, K. Liu, P. Xu, et al., “ACLY Promotes Gastric Tumorigenesis and Accelerates Peritoneal Metastasis of Gastric Cancer Regulated by HIF-1A,” Cell Cycle 22, no. 20 (2023): 2288–2301.
- 312X. Wei, J. Shi, Q. Lin, et al., “Corrigendum: Targeting ACLY Attenuates Tumor Growth and Acquired Cisplatin Resistance in Ovarian Cancer by Inhibiting the PI3K–AKT Pathway and Activating the AMPK–ROS Pathway,” Frontiers in Oncology 11 (2021): 642229.
- 313A. Ismail, H. A. Mokhlis, M. Sharaky, et al., “Hydroxycitric Acid Reverses Tamoxifen Resistance Through Inhibition of ATP Citrate Lyase,” Pathology—Research and Practice 240 (2022): 154211.
- 314W. Xiang, H. Lv, F. Xing, et al., “Inhibition of ACLY Overcomes Cancer Immunotherapy Resistance via Polyunsaturated Fatty Acids Peroxidation and cGAS-STING Activation,” Science Advances 9, no. 49 (2023): eadi2465.
- 315A. Ablasser and Z. J. Chen, “cGAS in Action: Expanding Roles in Immunity and Inflammation,” Science 363, no. 6431 (2019): eaat8657.
- 316D.-N. Li, W.-Q. Lu, B.-W. Yang, et al., “Atezolizumab Monotherapy or Plus Chemotherapy in First-Line Treatment for Advanced Non-Small Cell Lung Cancer Patients: A Meta-Analysis,” Frontiers in Immunology 12 (2021): 666909.
- 317P. Wang, T. Hou, F. Xu, et al., “Discovery of Flavonoids as Novel Inhibitors of ATP Citrate Lyase: Structure–Activity Relationship and Inhibition Profiles,” International Journal of Molecular Sciences 23, no. 18 (2022): 10747.
- 318J. Wei, S. Leit, J. Kuai, et al., “An Allosteric Mechanism for Potent Inhibition of Human ATP-Citrate Lyase,” Nature 568, no. 7753 (2019): 566–570.
- 319J. L. Li, J. Y. Jiang, S. S. Gu, et al., “Identification of Lignans as ATP Citrate Lyase (ACLY) Inhibitors From the Roots of Pouzolzia zeylanica,” Natural Product Research 38, no. 10 (2024): 1719–1726.
- 320J. Kaur and S. Bhattacharyya, “Cancer Stem Cells: Metabolic Characterization for Targeted Cancer Therapy,” Frontiers in Oncology 11 (2021): 756888.
- 321V. S. LeBleu, J. T. O'Connell, K. N. Gonzalez Herrera, et al., “PGC-1α Mediates Mitochondrial Biogenesis and Oxidative Phosphorylation in Cancer Cells to Promote Metastasis,” Nature Cell Biology 16, no. 10 (2014): 992–1003, 1–15.
- 322R. Zhu, X. Ye, X. Lu, et al., “ACSS2 Acts as a Lactyl-CoA Synthetase and Couples KAT2A to Function as a Lactyltransferase for Histone Lactylation and Tumor Immune Evasion,” Cell Metabolism 37, no. 2 (2025): 361–376.e7.
- 323S. Liu, H. Zhao, Y. Hu, et al., “Lactate Promotes Metastasis of Normoxic Colorectal Cancer Stem Cells Through PGC-1α-Mediated Oxidative Phosphorylation,” Cell Death & Disease 13, no. 7 (2022): 651.
- 324S. Alcalá, L. Villarino, L. Ruiz-Cañas, et al., “Targeting Cancer Stem Cell OXPHOS With Tailored Ruthenium Complexes as a New Anti-Cancer Strategy,” Journal of Experimental & Clinical Cancer Research 43, no. 1 (2024): 33.
- 325C. Raggi, M. L. Taddei, E. Sacco, et al., “Mitochondrial Oxidative Metabolism Contributes to a Cancer Stem Cell Phenotype in Cholangiocarcinoma,” Journal of Hepatology 74, no. 6 (2021): 1373–1385.
- 326M. H. Zahra, S. M. Afify, G. Hassan, et al., “Metformin Suppresses Self-Renewal and Stemness of Cancer Stem Cell Models Derived From Pluripotent Stem Cells,” Cell Biochemistry and Function 39, no. 7 (2021): 896–907.
- 327A. M. Stevens, E. S. Schafer, M. Li, et al., “Repurposing Atovaquone as a Therapeutic Against Acute Myeloid Leukemia (AML): Combination With Conventional Chemotherapy Is Feasible and Well Tolerated,” Cancers 15, no. 4 (2023): 1344.
- 328A. Kirtonia, G. Sethi, and M. Garg, “The Multifaceted Role of Reactive Oxygen Species in Tumorigenesis,” Cellular and Molecular Life Sciences 77, no. 22 (2020): 4459–4483.
- 329W. T. Chang, Y. D. Bow, Y. C. Chen, et al., “The Phenoxyphenol Compound diTFPP Mediates Exogenous C(2)-Ceramide Metabolism, Inducing Cell Apoptosis Accompanied by ROS Formation and Autophagy in Hepatocellular Carcinoma Cells,” Antioxidants 10, no. 3 (2021): 394.
- 330Y. Cao, J. Wang, H. Tian, and G. H. Fu, “Mitochondrial ROS Accumulation Inhibiting JAK2/STAT3 Pathway Is a Critical Modulator of CYT997-induced Autophagy and Apoptosis in Gastric Cancer,” Journal of Experimental & Clinical Cancer Research 39, no. 1 (2020): 119.
- 331V. I. Sayin, M. X. Ibrahim, E. Larsson, J. A. Nilsson, P. Lindahl, and M. O. Bergo, “Antioxidants Accelerate Lung Cancer Progression in Mice,” Science Translational Medicine 6, no. 221 (2014): 221ra15.
- 332J. Jorge, N. Magalhães, R. Alves, B. Lapa, A. C. Gonçalves, and A. B. Sarmento-Ribeiro, “Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation,” Biomedicines 10, no. 9 (2022): 2207.
- 333Z. Tian, Y. Yang, H. Wu, et al., “The Nrf2 Inhibitor Brusatol Synergistically Enhances the Cytotoxic Effect of Lapatinib in HER2-positive Cancers,” Heliyon 8, no. 8 (2022): e10410.
- 334Y. Liu, Y. Wang, J. Wang, et al., “Fangchinoline Suppresses Hepatocellular Carcinoma by Regulating ROS Accumulation via the TRIM7/Nrf2 Signaling Pathway,” Phytomedicine 135 (2024): 156143.
- 335M. Zhang, R. Song, Y. Liu, et al., “Calcium-Overload-Mediated Tumor Therapy by Calcium Peroxide Nanoparticles,” Chem 5, no. 8 (2019): 2171–2182.
- 336P. Zheng, B. Ding, Z. Jiang, et al., “Ultrasound-Augmented Mitochondrial Calcium Ion Overload by Calcium Nanomodulator to Induce Immunogenic Cell Death,” Nano Letters 21, no. 5 (2021): 2088–2093.
- 337M. Chang, L. Zhang, T. Zhang, et al., “Ultrasound-Augmented enzyodynamic-Ca(2+) Overload Synergetic Tumor Nanotherapy,” Biomaterials 307 (2024): 122513.
- 338J. Yang, P. Wang, X. Jiang, et al., “A Nanotherapy of Octanoic Acid Ameliorates Cardiac Arrest/Cardiopulmonary Resuscitation-Induced Brain Injury via RVG29- and Neutrophil Membrane-Mediated Injury Relay Targeting,” ACS Nano 17, no. 4 (2023): 3528–3548.
- 339B. Surnar, U. Basu, B. Banik, et al., “Nanotechnology-Mediated Crossing of Two Impermeable Membranes to Modulate the Stars of the Neurovascular Unit for Neuroprotection,” Proceedings of the National Academy of Sciences 115, no. 52 (2018): E12333–E12342.
- 340L. Li, Y. Lu, X. Xu, et al., “Catalytic-Enhanced Lactoferrin-Functionalized Au-Bi(2) Se(3) Nanodots for Parkinson's Disease Therapy via Reactive Oxygen Attenuation and Mitochondrial Protection,” Advanced Healthcare Materials 10, no. 13 (2021): e2100316.
- 341C. Zhang, Y. Cheng, D. Liu, et al., “Mitochondria-Targeted Cyclosporin A Delivery System to Treat Myocardial Ischemia Reperfusion Injury of Rats,” Journal of Nanobiotechnology 17, no. 1 (2019): 18.
- 342Y. Lin, J. Liu, R. Bai, et al., “Mitochondria-Inspired Nanoparticles With Microenvironment-Adapting Capacities for On-Demand Drug Delivery After Ischemic Injury,” ACS Nano 14, no. 9 (2020): 11846–11859.
- 343L. Jiang, J. S. Park, L. Yin, et al., “Dual mRNA Therapy Restores Metabolic Function in Long-Term Studies in Mice With Propionic Acidemia,” Nature Communications 11, no. 1 (2020): 5339.
- 344C. Hasselgren and T. I. Oprea, “Artificial Intelligence for Drug Discovery: Are We There Yet?,” Annual Review of Pharmacology and Toxicology 64 (2024): 527–550.
- 345J. Jumper, R. Evans, A. Pritzel, et al., “Highly Accurate Protein Structure Prediction With Alphafold,” Nature 596, no. 7873 (2021): 583–589.
- 346R. Qureshi, M. Irfan, T. M. Gondal, et al., “AI in Drug Discovery and Its Clinical Relevance,” Heliyon 9, no. 7 (2023): e17575.
- 347M. K. Tripathi, A. Nath, T. P. Singh, A. S. Ethayathulla, and P. Kaur, “Evolving Scenario of Big Data and Artificial Intelligence (AI) in Drug Discovery,” Molecular Diversity 25, no. 3 (2021): 1439–1460.
- 348F. Liu, X. Jiang, J. Yang, J. Tao, and M. Zhang, “A Chronotherapeutics-Applicable Multi-Target Therapeutics Based on AI: Example of Therapeutic Hypothermia,” Briefings in Bioinformatics 23, no. 5 (2022): bbac365.
- 349F. W. Pun, G. H. D. Leung, H. W. Leung, et al., “A Comprehensive AI-Driven Analysis of Large-Scale Omic Datasets Reveals Novel Dual-Purpose Targets for the Treatment of Cancer and Aging,” Aging Cell 22, no. 12 (2023): e14017.
- 350J. Haneczok, M. Delijewski, and R. Moldzio, “AI Molecular Property Prediction for Parkinson's Disease Reveals Potential Repurposing Drug Candidates Based on the increase of the Expression of PINK1,” Computer Methods and Programs in Biomedicine 241 (2023): 107731.
- 351A. A. A. Aljabali, M. El-Tanani, and M. M. Tambuwala, “Principles of CRISPR–Cas9 Technology: Advancements in Genome Editing and Emerging Trends in Drug Delivery,” Journal of Drug Delivery Science and Technology 92 (2024): 105338.
- 352H. X. Deng, H. Zhai, Y. Shi, et al., “Efficacy and Long-Term Safety of CRISPR/Cas9 Genome Editing in the SOD1-linked Mouse Models of ALS,” Communications Biology 4, no. 1 (2021): 396.
- 353J. Sun, J. Carlson-Stevermer, U. Das, et al., “CRISPR/Cas9 Editing of APP C-Terminus Attenuates β-Cleavage and Promotes Α-Cleavage,” Nature Communications 10, no. 1 (2019): 53.
- 354M. Mennuni, R. Filograna, A. Felser, et al., “Metabolic Resistance to the Inhibition of Mitochondrial Transcription Revealed by CRISPR–Cas9 Screen,” EMBO Reports 23, no. 1 (2022): e53054.
- 355S. R. A. Hussain, M. E. Yalvac, B. Khoo, S. Eckardt, and K. J. McLaughlin, “Adapting CRISPR/Cas9 System for Targeting Mitochondrial Genome,” Frontiers in Genetics 12 (2021): 627050.
