Disruption of mitochondrial bioenergetics, calcium retention capacity and cell viability caused by D-2-hydroxyglutaric acid in the heart.

Abstract

Accumulation of D-2-hydroxyglutaric acid (D-2-HG) is the biochemical hallmark of D-2-hydroxyglutaric aciduria type I and, particularly, of D-2-hydroxyglutaric aciduria type II (D2HGA2). D2HGA2 is a metabolic inherited disease caused by gain-of-function mutations in the gene isocitrate dehydrogenase 2. It is clinically characterized by neurological abnormalities and a severe cardiomyopathy whose pathogenesis is still poorly established. The present work investigated the potential cardiotoxicity D-2-HG, by studying its in vitro effects on a large spectrum of bioenergetics parameters in heart of young rats and in cultivated H9c2 cardiac myoblasts. D-2-HG impaired cellular respiration in purified mitochondrial preparations and crude homogenates from heart of young rats, as well as in digitonin-permeabilized H9c2 cells. ATP production and the activities of cytochrome c oxidase (complex IV), alpha-ketoglutarate dehydrogenase, citrate synthase and creatine kinase were also inhibited by D-2-HG, whereas the activities of complexes I, II and II-III of the respiratory chain, glutamate, succinate and malate dehydrogenases were not altered. We also found that this organic acid compromised mitochondrial Ca2+ retention capacity in heart mitochondrial preparations and H9c2 myoblasts. Finally, D-2-HG reduced the viability of H9c2 cardiac myoblasts, as determined by the MTT test and by propidium iodide incorporation. Noteworthy, L-2-hydroxyglutaric acid did not change some of these measurements (complex IV and creatine kinase activities) in heart preparations, indicating a selective inhibitory effect of the enantiomer D. In conclusion, it is presumed that D-2-HG-disrupts mitochondrial bioenergetics and Ca2+ retention capacity, which may be involved in the cardiomyopathy commonly observed in D2HGA2.

• Authors: Rafael Teixeira Ribeiro, Ana Cristina Roginski, Rafael Aguiar Marschner, Simone Magagnin Wajner, Roger Frigério Castilho, Alexandre Umpierrez Amaral, Moacir Wajner
• Journal: Biochimie (Biochimie) Vol. 207 Pg. 153-164 (Apr 2023) ISSN: 1638-6183 [Electronic] France
• PMID: 36372308 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Chemical References

• alpha-hydroxyglutarate
• Calcium
• Creatine Kinase

Topics

• Rats
• Animals
• Calcium (metabolism)
• Cell Survival
• Energy Metabolism
• Creatine Kinase (metabolism)
• Cardiomyopathies