Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms

Significance Pathogenic mtDNA tRNA mutations, such as the 3243A>G MELAS mutation, generally result in multisystem failure. In cybrids harboring ∼70% 3243G mutant mtDNA, the mitochondrial unfolded protein response (UPR mt ) is impaired. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1, or CHCHD2) is a bi-organellar (mitochondrial and nuclear) protein that is reduced in ∼70% 3243G cybrid cells. Under stress conditions, MNRR1 import into mitochondria is impaired, resulting in its preferential concentration in the nucleus. Increased nuclear MNRR1 induces the UPR mt through regulation of the ATF5 transcription factor. Overexpression of MNRR1 in ∼70% 3243G cybrid cells induces the UPR mt , autophagy, and mitochondrial biogenesis and restores mitochondrial respiratory function; furthermore, the proportion of wild-type mtDNA increases. Thus, MNRR1 overexpression might be beneficial for mtDNA diseases.