title: Branched chain keto-acids exert biphasic effects on alpha-ketoglutarate-stimulated respiration in intact rat liver mitochondria.
abstract: Pathophysiological concentrations of branched chain keto-acids (BCKAs), such as those that occur in maple syrup urine disease, inhibit oxygen consumption in liver homogenates and brain slices and the enzymatic activity of alpha-ketoglutarate- and pyruvate dehydrogenase complexes. Consistent with previous work, studies in isolated rat liver mitochondria indicate that three BCKAs, alpha-ketoisocaproate (KIC), alpha-keto-beta-methylvalerate (KMV) and alpha-ketoisovalerate (KIV), preferentially inhibited State 3 respiration supported by alpha-ketoglutarate relative to succinate or glutamate/malate (KIC, >100-fold; KMV, >10-fold; KIV, >4-fold). KIC was also the most potent inhibitor (K(i,app) 13 +/- 2 muM). Surprisingly, sub-inhibitory concentrations of KIC and KMV can markedly stimulate State 3 respiration of mitochondria utilizing alpha-ketoglutarate and glutamate/malate, but not succinate. The data suggest that physiological concentrations of the BCKAs may modulate mitochondrial respiration.
authors.affiliation: Dementia Research Service, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Shestopalov
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
mesh_terms: D000818:Animals; D066298:In Vitro Techniques; D007651:Keto Acids / Q000737:chemistry / Q000494:pharmacology*; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D011048:Polarography; D051381:Rats; D011916:Rats, Inbred F344; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship
chemical_list: D007651:Keto Acids; D007656:Ketoglutaric Acids; D007655:Ketoglutarate Dehydrogenase Complex