Disturbance of bioenergetics and calcium homeostasis provoked by metabolites accumulating in propionic acidemia in heart mitochondria of developing rats

Author(s)

Roginski, Ana Cristina ^[1] ; Wajner, Alessandro ^[1] ; Cecatto, Cristiane ^[1] ; Wajner, Simone Magagnin ^[2] ; Castilho, Roger Frigerio ^[3] ; Wajner, Moacir ^{[4, 1, 5]} ; Amaral, Alexandre Umpierrez ^{[1, 5, 6]}

Affiliation

^[1] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Programa Posgrad Ciencias Biol Bioquim, Porto Alegre, RS - Brazil

^[2] Univ Fed Rio Grande do Sul, Fac Med, Dept Med Interna, Porto Alegre, RS - Brazil

^[3] Univ Estadual Campinas, Fac Ciencias Med, Dept Patol Clin, Campinas, SP - Brazil

^[4] Hosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS - Brazil

^[5] Univ Fed Rio Grande do Sul, Inst Ciencias Basicas Saude, Dept Bioquim, Porto Alegre, RS - Brazil

^[6] Univ Reg Integrada Alto Uruguai & Missoes, Dept Ciencias Biol, Ave Sete Setembro 1621, BR-99709910 Erechim, RS - Brazil

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE; v. 1866, n. 5 MAY 1 2020.
• Web of Science Citations: 0

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 alpha-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 alpha-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 (Delta Psi m), NAD(P)H content and Ca2+ retention capacity, and caused swelling in Ca2+-loaded mitochondria. Noteworthy, Delta Psi m 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. (AU)

• FAPESP's process: 17/17728-8 - Mitochondrial function and dysfunction: implications for aging and associated diseases
• Grantee: Aníbal Eugênio Vercesi
• Support Opportunities: Research Projects - Thematic Grants