Mitochondrial dysfunction in inborn errors of metabolism

Abstract Inborn errors of metabolism (IEM) result in metabolic blockage and accumulation of substrate and metabolites, with subsequent shortage of metabolic products. IEM are responsible for developmental deficiencies in childhood and also death of affected patients. The pathophysiological mechanisms of most of these diseases are still unclear, resulting in poor or unsatisfactory therapies. Mitochondrial dysfunction has been consistently implicated as a key factor in the pathophysiology of many IEM. Even discrete disruptions of mitochondrial homeostasis may lead to cellular damage and ultimately cell death. Possible mechanisms in IEM pathology include energy metabolism disturbance, calcium dyshomeostasis, redox imbalance, and alterations in mitochondrial dynamics. Many of these events may act together and even synergistically to exacerbate the disabilities seen in patients affected by different IEM. We herein summarize evidence of mitochondrial involvement in the pathophysiology of IEM, spanning from primary mitochondrial deficits to cell damage elicited by secondary mitochondrial involvement.