maleic-acid and Propionic-Acidemia

Propionic acid (PA) predominantly accumulates in tissues and biological fluids of patients affected by propionic acidemia that may manifest chronic renal failure along development. High urinary excretion of maleic acid (MA) has also been described. Considering that the underlying mechanisms of renal dysfunction in this disorder are poorly known, the present work investigated the effects of PA and MA (1-5 mM) on mitochondrial functions and cellular viability in rat kidney and cultured human embryonic kidney (HEK-293) cells. Mitochondrial membrane potential (∆ψm), NAD(P)H content, swelling and ATP production were measured in rat kidney mitochondrial preparations supported by glutamate or glutamate plus malate, in the presence or absence of Ca

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Calcium; Cyclosporine; Glutamic Acid; HEK293 Cells; Humans; Kidney; Kidney Failure, Chronic; Malates; Maleates; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; NAD; Permeability; Propidium; Propionic Acidemia; Rats; Rats, Wistar

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 Ca

Topics: Animals; Calcium; Cardiomyopathies; Cell Fractionation; Cell Line; Energy Metabolism; Humans; Male; Maleates; Mitochondria, Heart; Mitochondrial Swelling; Myoblasts, Cardiac; Oxygen; Propionates; Propionic Acidemia; Rats