Mic60 is essential to maintain mitochondrial integrity and to prevent encephalomyopathy

Mitochondrial encephalomyopathies (ME) are frequently associated with mutations of mitochondrial DNA, but the pathogenesis of a subset of ME (sME) remains elusive. Here we report that haploinsufficiency of a mitochondrial inner membrane protein, Mic60, causes progressive neurological abnormalities with insulted mitochondrial structure and neuronal loss in mice. In addition, haploinsufficiency of Mic60 reduces mitochondrial membrane potential and cellular ATP production, increases reactive oxygen species, and alters mitochondrial oxidative phosphorylation complexes in neurons in an age-dependent manner. Moreover, haploinsufficiency of Mic60 compromises brain glucose intake and oxygen consumption in mice, resembling human ME syndrome. We further discover that MIC60 protein expression declined significantly in human sME, implying that insufficient MIC60 may contribute for pathogenesis of human ME. Notably, systemic administration of antioxidant N-acetylcysteine largely reverses mitochondrial dysfunctions and metabolic disorders in haplo-insufficient Mic60 mice, also restores neurological abnormal symptom. These results reveal Mic60 is required in the maintenance of mitochondrial integrity and function, and likely a potential therapeutics target for mitochondrial encephalomyopathies.

Automated summary

Haploinsufficiency of Mic60, a mitochondrial inner membrane protein, leads to progressive neurological abnormalities, mitochondrial structural damage, neuronal loss, reduced mitochondrial membrane potential and ATP production, increased reactive oxygen species, and altered oxidative phosphorylation complexes. It also compromises brain glucose intake and oxygen consumption, resembling human mitochondrial encephalomyopathies (ME) syndrome. MIC60 protein expression is significantly decreased in human ME, suggesting its contribution to the pathogenesis. Systemic administration of N-acetylcysteine, an antioxidant, reverses mitochondrial dysfunctions and metabolic disorders in mice with Mic60 haploinsufficiency and restores neurological symptoms.