Drug-induced mitochondrial neuropathy in children: A conceptual framework for critical windows of development

Mitochondrial disease arises from genetic or nongenetic events that interfere either directly or indirectly with the bioenergetic function of the mitochondrion and manifest clinically in some form of metabolic disorder. In primary mitochondrial disease, the critical molecular target is one or more of the individual subunits of the respiratory complexes or their assembly and incorporation into the inner mitochondrial membrane, whereas with secondary mitochondrial disease the bioenergetic deficits are secondary to effects on targets other than the electron transport chain and oxidative phosphorylation. Primary genetic events include mutations to or altered expression of proteins targeted to the mitochondrial compartment, whether they are encoded by the nuclear or mitochondrial genome. In this review, we emphasize the occurrence of nongenetic mitochondrial disease resulting from therapeutic drug administration, review the broad scope of drugs implicated in affecting specific primary mitochondrial targets, and describe evidence demonstrating critical windows of risk for the developing neonate to drug-induced mitochondrial disease and neuropathy.