Roginski 2020 Biochim Biophys Acta Mol Basis Dis

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Roginski AC, Wajner A, Cecatto C, Wajner SM, Castilho RF, Wajner M, Amaral AU (2020) Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats. Biochim Biophys Acta Mol Basis Dis 1866:165682.

» PMID: 31931102

Roginski AC, Wajner A, Cecatto C, Wajner SM, Castilho RF, Wajner M, Amaral AU (2020) Biochim Biophys Acta Mol Basis Dis

Abstract: 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.

Copyright © 2020 Elsevier B.V. All rights reserved.

Keywords: Cardiomyopathy, Maleic acid, Mitochondrial functions, Propionic acid, Propionic acidemia Bioblast editor: Plangger M O2k-Network Lab: BR Porto Alegre Souza DOG


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Inherited  Stress:Permeability transition  Organism: Rat  Tissue;cell: Heart, Other cell lines  Preparation: Permeabilized cells, Homogenate, Isolated mitochondria 


Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k 

Labels, 2020-01