Methylmalonate inhibits succinate-supported oxygen consumption by interfering with mitochondrial succinate uptake.
The effect of methylmalonate (MMA) on mitochondrial succinate oxidation has received great attention since it could present an important role in energy metabolism impairment in methylmalonic acidaemia. In the present work, we show that while millimolar concentrations of MMA inhibit succinate-supported oxygen consumption by isolated rat brain or muscle mitochondria, there is no effect when either a pool of NADH-linked substrates or N,N,N',N'-tetramethyl-p-phenylendiamine (TMPD)/ascorbate were used as electron donors. Interestingly, the inhibitory effect of MMA, but not of malonate, on succinate-supported brain mitochondrial oxygen consumption was minimized when nonselective permeabilization of mitochondrial membranes was induced by alamethicin. In addition, only a slight inhibitory effect of MMA was observed on succinate-supported oxygen consumption by inside-out submitochondrial particles. In agreement with these observations, brain mitochondrial swelling experiments indicate that MMA is an important inhibitor of succinate transport by the dicarboxylate carrier. Under our experimental conditions, there was no evidence of malonate production in MMA-treated mitochondria. We conclude that MMA inhibits succinate-supported mitochondrial oxygen consumption by interfering with the uptake of this substrate. Although succinate generated outside the mitochondria is probably not a sig-nificant contributor to mitochondrial energy generation, the physiopathological implications of MMA-induced inhibition of substrate transport by the mitochondrial dicarboxylate carrier are discussed.
Mirandola
S R
SR
Departamento de Patologia Clínica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP 13083-887, Brazil.
Melo
D R
DR
Schuck
P F
PF
Ferreira
G C
GC
Wajner
M
M
Castilho
R F
RF
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D029382:Dicarboxylic Acid Transporters / Q000037:antagonists & inhibitors; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D008314:Malonates / Q000378:metabolism; D008764:Methylmalonic Acid / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009924:Organ Culture Techniques; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013385:Succinate Dehydrogenase / Q000378:metabolism; D019802:Succinic Acid / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*
D029382:Dicarboxylic Acid Transporters; D008314:Malonates; D008764:Methylmalonic Acid; C030290:malonic acid; D019802:Succinic Acid; D013385:Succinate Dehydrogenase