Propionic acidemia is caused by lack of
propionyl-CoA carboxylase activity. It is biochemically characterized by accumulation of propionic (PA) and 3-hydroxypropionic (3OHPA)
acids and clinically by severe
encephalopathy and
cardiomyopathy. High urinary excretion of
maleic acid (MA) and
2-methylcitric acid (2MCA) is also found in the affected patients. Considering that the underlying mechanisms of
cardiac disease in
propionic acidemia are practically unknown, we investigated the effects of PA, 3OHPA, MA and 2MCA (0.05-5 mM) on important mitochondrial functions in isolated rat heart mitochondria, as well as in crude heart homogenates and cultured cardiomyocytes. MA markedly inhibited state 3 (
ADP-stimulated), state 4 (non-phosphorylating) and uncoupled (
CCCP-stimulated) respiration in mitochondria supported by
pyruvate plus
malate or α-ketoglutarate associated with reduced
ATP production, whereas PA and 3OHPA provoked less intense inhibitory effects and 2MCA no alterations at all. MA-induced impaired respiration was attenuated by
coenzyme A supplementation. In addition, MA significantly inhibited α-ketoglutarate
dehydrogenase activity. Similar data were obtained in heart crude homogenates and permeabilized cardiomyocytes. MA, and PA to a lesser degree, also decreased mitochondrial membrane potential (ΔΨm),
NAD(P)H content and Ca2+ retention capacity, and caused swelling in Ca2+-loaded mitochondria. Noteworthy, ΔΨm collapse and mitochondrial swelling were fully prevented or attenuated by
cyclosporin A and
ADP, indicating the involvement of mitochondrial permeability transition. It is therefore proposed that disturbance of mitochondrial energy and
calcium homeostasis caused by MA, as well as by PA and 3OHPA to a lesser extent, may be involved in the
cardiomyopathy commonly affecting propionic acidemic patients.