Disturbances of Mitochondrial Functions and Oxidative Stress Induction in Methylmalonic and Propionic Acidemias: A Critical Role for Metabolite Accumulation.

Methylmalonic and propionic acidemias are inherited disorders of propionyl-CoA catabolism characterized by deficient activity of L-methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. They lead to metabolite accumulation in tissues and biological fluids, including methylmalonic, propionic, 3-hydroxypropionic, 2-methylcitric and maleic acids. Affected patients develop multi-systemic symptoms, with predominant neurological manifestations. Although current therapy based on dietary protein restriction significantly decreases mortality and morbidity, it is still insufficient to prevent long-term complications in most patients. The pathogenesis of methylmalonic and propionic acidemias has been investigated in recent decades using chemically induced in vivo models, genetic animal models, in vitro models and tissues and biological fluids from patients. Although the precise mechanisms responsible for the clinical manifestations in these disorders remain under debate, biomarkers of mitochondrial dysfunction and oxidative stress have been consistently described in tissues from affected patients and genetic murine models. Notably, growing evidence indicates that the organic acids accumulating in these disorders, which are formed within mitochondria, compromise mitochondrial functions through multiple mechanisms, disrupting bioenergetics, quality control, calcium homeostasis and redox balance, ultimately leading to cell death. This review discusses pathomechanisms of mitotoxicity caused by the major organic acids accumulating in methylmalonic and propionic acidemias from observations taken from patients and animal models.