Mitochondrial dysfunction is involved in the aggravation of periodontitis by diabetes
Xiaoyu Sun
Department of Periodontology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Contribute equally to this paper.Search for more papers by this authorYixin Mao
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Contribute equally to this paper.Search for more papers by this authorPanpan Dai
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Contribute equally to this paper.Search for more papers by this authorXumin Li
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorWeiyan Gu
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorHuining Wang
Department of Periodontology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorCorresponding Author
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Jianfeng Ma
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Shengbin Huang
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorXiaoyu Sun
Department of Periodontology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Contribute equally to this paper.Search for more papers by this authorYixin Mao
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Contribute equally to this paper.Search for more papers by this authorPanpan Dai
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Contribute equally to this paper.Search for more papers by this authorXumin Li
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorWeiyan Gu
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorHuining Wang
Department of Periodontology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Search for more papers by this authorCorresponding Author
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Jianfeng Ma
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorCorresponding Author
Shengbin Huang
Institute of Stomatology, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Department of Oral Implantology and Prosthetic Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands
Department of Prosthodontics, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, China
Address:
Gang Wu
Department of Oral Implantology and Prosthetic Dentistry
Academic Centre for Dentistry Amsterdam (ACTA)
VU University Amsterdam and University of Amsterdam
MOVE Research Institute
Amsterdam 1081 LA
the Netherlands
E-mail: [email protected]
Jianfeng Ma
Department of Prosthodontics
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Shengbin Huang
Institute of Stomatology
School and Hospital of Stomatology
Wenzhou Medical University
No. 373, Xueyuan West Road
Lucheng District
Wenzhou, China
E-mail: [email protected]
Search for more papers by this authorConflict of interest and source of funding statement
The authors declare that they have no conflict of interests.
This research was supported in part by the Natural Science Foundation of China (No. 81500817), Zhejiang Provincial Natural Science Foundation of China (No. LY15H140008, LY16H140005), Health Science and Technology Project of Zhejiang Province (2016KYB184), Wenzhou Public Technical Research Medical Program (NO. Y20140708), and Wenzhou Technology Bureau Project (Y20160402).
Abstract
Aim
To elucidate whether mitochondrial dysfunction contributes to aggravated periodontitis in diabetes.
Materials and Methods
Sixty-four wistar rats were randomly assigned into four groups: control, periodontitis, diabetes, and diabetic periodontitis. Two weeks after induction of diabetes, periodontitis was induced by silk ligation for 2 weeks and thereafter evaluated by assessing alveolar bone loss and apoptosis of periodontium cells. Mitochondrial oxidative stress was detected by MitoSOX staining. Mitochondrial function was determined by measuring ATP production, and by assessing mitochondrial DNA copy number, activities of electron transport chain complexes, and biogenesis with real-time PCR.
Results
Significantly severer bone loss, enhanced periodontium cell apoptosis, and mitochondrial oxidative stress were found in the rats with diabetic periodontitis than the others. Furthermore, diabetic rats with periodontitis presented severer mitochondrial dysfunction than lean rats with periodontitis, as reflected by compromised ATP production, decreased mitochondrial DNA copy number, reduced gene expression of electron transport chain complex I subunits, and impaired mitochondrial biogenesis (p < 0.05). Multiple regression analysis further indicated a close correlation between these mitochondrial events and bone loss in diabetic periodontitis.
Conclusions
Mitochondrial dysfunction was positive correlated to aggravated periodontitis in diabetes and might represent a therapeutic target for diabetic periodontitis.
References
- Akalin, F. A., Isiksal, E., Baltacioglu, E., Renda, N. & Karabulut, E. (2008) Superoxide dismutase activity in gingiva in type-2 diabetes mellitus patients with chronic periodontitis. Archives of Oral Biology 53, 44–52.
- Allen, E. M., Matthews, J. B., DJ, O. H., Griffiths, H. R. & Chapple, I. L. (2011) Oxidative and inflammatory status in Type 2 diabetes patients with periodontitis. Journal of Clinical Periodontology 38, 894–901.
- Aspriello, S. D., Zizzi, A., Tirabassi, G., Buldreghini, E., Biscotti, T., Faloia, E., Stramazzotti, D., Boscaro, M. & Piemontese, M. (2011) Diabetes mellitus-associated periodontitis: differences between type 1 and type 2 diabetes mellitus. Journal of Periodontal Research 46, 164–169.
- Balci Yuce, H., Toker, H. & Goze, F. (2014) The histopathological and morphometric investigation of the effects of systemically administered boric acid on alveolar bone loss in ligature-induced periodontitis in diabetic rats. Acta Odontologica Scandinavica 72, 729–736.
- Bascones-Martinez, A., Munoz-Corcuera, M. & Bascones-Ilundain, J. (2015) Diabetes and periodontitis: a bidirectional relationship. Medicina Clínica 145, 31–35.
- Botero, J. E., Yepes, F. L., Roldan, N., Castrillon, C. A., Hincapie, J. P., Ochoa, S. P., Ospina, C. A., Becerra, M. A., Jaramillo, A., Gutierrez, S. J. & Contreras, A. (2012) Tooth and periodontal clinical attachment loss are associated with hyperglycemia in patients with diabetes. Journal of Periodontology 83, 1245–1250.
- Bullon, P., Cordero, M. D., Quiles, J. L., Morillo, J. M., del Carmen Ramirez-Tortosa, M. & Battino, M. (2011) Mitochondrial dysfunction promoted by Porphyromonas gingivalis lipopolysaccharide as a possible link between cardiovascular disease and periodontitis. Free Radical Biology and Medicine 50, 1336–1343.
- Bullon, P., Newman, H. N. & Battino, M. (2014) Obesity, diabetes mellitus, atherosclerosis and chronic periodontitis: a shared pathology via oxidative stress and mitochondrial dysfunction? Periodontology 2000 64, 139–153.
- Bullon, P., Roman-Malo, L., Marin-Aguilar, F., Alvarez-Suarez, J. M., Giampieri, F., Battino, M. & Cordero, M. D. (2015) Lipophilic antioxidants prevent lipopolysaccharide-induced mitochondrial dysfunction through mitochondrial biogenesis improvement. Pharmacological Research 91, 1–8.
- Cai, X., Li, C., Du, G. & Cao, Z. (2008) Protective effects of baicalin on ligature-induced periodontitis in rats. Journal of Periodontal Research 43, 14–21.
- Canakci, C. F., Tatar, A., Canakci, V., Cicek, Y., Oztas, S. & Orbak, R. (2006) New evidence of premature oxidative DNA damage: mitochondrial DNA deletion in gingival tissue of patients with periodontitis. Journal of Periodontology 77, 1894–1900.
- Chapple, I. L. (1997) Reactive oxygen species and antioxidants in inflammatory diseases. Journal of Clinical Periodontology 24, 287–296.
- Clay Montier, L. L., Deng, J. J. & Bai, Y. (2009) Number matters: control of mammalian mitochondrial DNA copy number. Journal of Genetics and Genomics 36, 125–131.
- Crawford, J. M., Taubman, M. A. & Smith, D. J. (1978) The natural history of periodontal bone loss in germfree and gnotobiotic rats infected with periodontopathic microorganisms. Journal of Periodontal Research 13, 316–325.
- Eke, P. I., Zhang, X., Lu, H., Wei, L., Thornton-Evans, G., Greenlund, K. J., Holt, J. B. & Croft, J. B. (2016) Predicting periodontitis at state and local levels in the United States. Journal of Dental Research 95, 515–522.
- Etminan, N. & Rinkel, G. J. (2015) Cerebral aneurysms: cerebral aneurysm guidelines-more guidance needed. Nature Reviews. Neurology 11, 490–491.
- Fu, Y. W. & He, H. B. (2013) Apoptosis of periodontium cells in streptozototocin- and ligature-induced experimental diabetic periodontitis in rats. Acta Odontologica Scandinavica 71, 1206–1215.
- Govindaraj, P., Khan, N. A., Gopalakrishna, P., Chandra, R. V., Vanniarajan, A., Reddy, A. A., Singh, S., Kumaresan, R., Srinivas, G., Singh, L. & Thangaraj, K. (2011) Mitochondrial dysfunction and genetic heterogeneity in chronic periodontitis. Mitochondrion 11, 504–512.
- Graves, D. T., Liu, R., Alikhani, M., Al-Mashat, H. & Trackman, P. C. (2006) Diabetes-enhanced inflammation and apoptosis–impact on periodontal pathology. Journal of Dental Research 85, 15–21.
- Gurav, A. N. (2016) Management of diabolical diabetes mellitus and periodontitis nexus: Are we doing enough? World Journal of Diabetes 7, 50–66.
- Huang, S., Wang, Y., Gan, X., Fang, D., Zhong, C., Wu, L., Hu, G., Sosunov, A. A., McKhann, G. M., Yu, H. & Yan, S. S. (2015) Drp1-mediated mitochondrial abnormalities link to synaptic injury in diabetes model. Diabetes 64, 1728–1742.
- Hyeon, S., Lee, H., Yang, Y. & Jeong, W. (2013) Nrf2 deficiency induces oxidative stress and promotes RANKL-induced osteoclast differentiation. Free Radical Biology and Medicine 65, 789–799.
- Jimenez, M., Hu, F. B., Marino, M., Li, Y. & Joshipura, K. J. (2012) Type 2 diabetes mellitus and 20 year incidence of periodontitis and tooth loss. Diabetes Research and Clinical Practice 98, 494–500.
- Kezic, A., Spasojevic, I., Lezaic, V. & Bajcetic, M. (2016) Mitochondria-targeted antioxidants: future perspectives in kidney ischemia reperfusion injury. Oxidative Medicine and Cellular Longevity 2016, 2950503.
- Kose, O., Arabaci, T., Kara, A., Yemenoglu, H., Kermen, E., Kizildag, A., Gedikli, S. & Ozkanlar, S. (2016) Effects of melatonin on oxidative stress index and alveolar bone loss in diabetic rats with periodontitis. Journal of Periodontology 87, e82–e90.
- Lim, S., Rashid, M. A., Jang, M., Kim, Y., Won, H., Lee, J., Woo, J. T., Kim, Y. S., Murphy, M. P., Ali, L., Ha, J. & Kim, S. S. (2011) Mitochondria-targeted antioxidants protect pancreatic beta-cells against oxidative stress and improve insulin secretion in glucotoxicity and glucolipotoxicity. Cellular Physiology and Biochemistry 28, 873–886.
- Liu, L., Li, C., Cai, X., Xiang, J., Cao, Z. & Dong, W. (2010a) The temporal expression and localization of extracellular matrix metalloproteinase inducer (EMMPRIN) during the development of periodontitis in an animal model. Journal of Periodontal Research 45, 541–549.
- Liu, S., Cheng, Y., Fan, M., Chen, D. & Bian, Z. (2010b) FSH aggravates periodontitis-related bone loss in ovariectomized rats. Journal of Dental Research 89, 366–371.
- Lustgarten, M. S., Bhattacharya, A., Muller, F. L., Jang, Y. C., Shimizu, T., Shirasawa, T., Richardson, A. & Van Remmen, H. (2012) Complex I generated, mitochondrial matrix-directed superoxide is released from the mitochondria through voltage dependent anion channels. Biochemical and Biophysical Research Communications 422, 515–521.
- Ma, Q. (2013) Role of nrf2 in oxidative stress and toxicity. Annual Review of Pharmacology and Toxicology 53, 401–426.
- Maekawa, S., Katagiri, S., Takeuchi, Y., Komazaki, R., Ohtsu, A., Udagawa, S. & Izumi, Y. (2016). Bone metabolic microarray analysis of ligature-induced periodontitis in streptozotocin-induced diabetic mice. Journal of Periodontal Research, doi:10.1111/jre.12387, [Epub ahead of print].
- Malik, A. N. & Czajka, A. (2013) Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13, 481–492.
- Mazzanti, R. & Giulivi, C. (2006) Coordination of nuclear- and mitochondrial-DNA encoded proteins in cancer and normal colon tissues. Biochimica et Biophysica Acta 1757, 618–623.
- Mikhed, Y., Daiber, A. & Steven, S. (2015) Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. International Journal of Molecular Sciences 16, 15918–15953.
- Musatov, A. & Robinson, N. C. (2012) Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase. Free Radical Research 46, 1313–1326.
- Pallavi, T., Chandra, R. V., Reddy, A. A., Reddy, B. H. & Naveen, A. (2016) Identical mitochondrial somatic mutations unique to chronic periodontitis and coronary artery disease. Journal of Indian Society of Periodontology 20, 17–21.
- Palmeira, C. M., Rolo, A. P., Berthiaume, J., Bjork, J. A. & Wallace, K. B. (2007) Hyperglycemia decreases mitochondrial function: the regulatory role of mitochondrial biogenesis. Toxicology and Applied Pharmacology 225, 214–220.
- Patil, V. S., Patil, V. P., Gokhale, N., Acharya, A. & Kangokar, P. (2016) Chronic periodontitis in type 2 diabetes mellitus: oxidative stress as a common factor in periodontal tissue injury. Journal of Clinical and Diagnostic Research 10, Bc12–Bc16.
- Pendyala, G., Thomas, B. & Joshi, S. R. (2013) Evaluation of total antioxidant capacity of saliva in type 2 diabetic patients with and without periodontal disease: a case-control study. North American Journal of Medical Sciences 5, 51–57.
- Prakash, C. & Kumar, V. (2016) Chronic arsenic exposure-induced oxidative stress is mediated by decreased mitochondrial biogenesis in rat liver. Biological Trace Element Research 173, 87–95.
- Rommelaere, G., Michel, S., Mercy, L., Fattaccioli, A., Demazy, C., Ninane, N., Houbion, A., Renard, P. & Arnould, T. (2011) Hypersensitivity of mtDNA-depleted cells to staurosporine-induced apoptosis: roles of Bcl-2 downregulation and cathepsin B. American Journal of Physiology. Cell Physiology 300, C1090–C1106.
- Sanders, A. E., Sofer, T., Wong, Q., Kerr, K. F., Agler, C., Shaffer, J. R., Beck, J. D., Offenbacher, S., Salazar, C. R., North, K. E., Marazita, M. L., Laurie, C. C., Singer, R. H., Cai, J., Finlayson, T. L. & Divaris, K. (2017). Chronic periodontitis genome-wide association study in the Hispanic community health study/study of Latinos. Journal of Dental Research, 96, 64–72. doi:10.1177/0022034516664509
- Sharma, D. R., Sunkaria, A., Wani, W. Y., Sharma, R. K., Kandimalla, R. J., Bal, A. & Gill, K. D. (2013) Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1alpha expression. Toxicology and Applied Pharmacology 273, 365–380.
- Singh, S. P., Schragenheim, J., Cao, J., Falck, J. R., Abraham, N. G. & Bellner, L. (2016) PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: role of epoxyeicosatrienoic acid. Prostaglandins & Other Lipid Mediators 125, 8–18.
- Tait, S. W. & Green, D. R. (2012) Mitochondria and cell signalling. Journal of Cell Science 125, 807–815.
- Tamaki, N., Cristina Orihuela-Campos, R., Inagaki, Y., Fukui, M., Nagata, T. & Ito, H. O. (2014) Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model. Free Radical Biology and Medicine 75, 222–229.
- Tonetti, M. S., Schmid, J., Hammerle, C. H. & Lang, N. P. (1993) Intraepithelial antigen-presenting cells in the keratitied mucosa around teeth and osseointegrated implants. Clinical Oral Implants Research 4, 177–186.
- Valls-Lacalle, L., Barba, I., Miro-Casas, E., Alburquerque-Bejar, J. J., Ruiz-Meana, M., Fuertes-Agudo, M., Rodriguez-Sinovas, A. & Garcia-Dorado, D. (2016) Succinate dehydrogenase inhibition with malonate during reperfusion reduces infarct size by preventing mitochondrial permeability transition. Cardiovascular Research 109, 374–384.
- Wang, H., Bei, Y., Lu, Y., Sun, W., Liu, Q., Wang, Y., Cao, Y., Chen, P., Xiao, J. & Kong, X. (2015) Exercise prevents cardiac injury and improves mitochondrial biogenesis in advanced diabetic cardiomyopathy with PGC-1alpha and Akt activation. Cellular Physiology and Biochemistry 35, 2159–2168.
- Wang, X. (2001) The expanding role of mitochondria in apoptosis. Genes & Development 15, 2922–2933.
- Xu, Y., Miriyala, S., Fang, F., Bakthavatchalu, V., Noel, T., Schell, D. M., Wang, C., St Clair, W. H. & St Clair, D. K. (2015) Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect. Oncogene 34, 4229–4237.
- Yu, E. P., & Bennett, M. R. (2016). The role of mitochondrial DNA damage in the development of atherosclerosis. Free Radical Biology and Medicine, 100, 223–230. doi:10.1016/j.freeradbiomed.2016.06.011
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