Assessment of mitochondrial function in vivo with a breath test utilizing α—ketoisocaproic acid

A breath test to assess hepatic mitochondrial function in vivo was evaluated in rats. Following the i.p. administration of [1-¹⁴C]-α-ketoisocaproic acid, ¹⁴CO₂ exhalation reached a peak within 10 to 20 min and then declined exponentially, with a half-life of 14.3 min. Control animals exhaled 38.6% of the administered radioactivity within 1 hr. In functionally anhepatic animals, ¹⁴CO₂ in breath amounted to 23% of that in control animals, indicating that α-ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo. Ethanol (3 gm per kg) significantly decreased α-ketoisocaproic acid decarboxylation (21.8% of the dose appearing in breath in 1 hr), probably due to the ethanol-induced shift in the NAD⁺:NADH ratio. In contrast, an uncoupler of mitochondrial respiration, sodium salicylate (375 mg per kg), increased the decarboxylation of α—ketoisocaproic acid (56.3% of the dose recovered as ¹⁴CO₂ in 1 hr). Mitochondrial damage induced by 4-pentenoic acid decreased the decarboxylation of α-ketoisocaproic acid but did not affect the microsomal metabolism of antipyrine. The present data indicate that the α-ketoisocaproic acid breath test provides a noninvasive estimate of hepatic mitochondrial function in vivo which, when applied to man, might yield clinically useful information.