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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,12,15]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Pathogenic mtDNA tRNA mutations, such as the 3243A&gt;G MELAS mutation, generally result in multisystem failure. In cybrids harboring \u223c70% 3243G mutant mtDNA, the mitochondrial unfolded protein response (UPR\n                    <jats:sup>mt<\/jats:sup>\n                    ) is impaired. Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1, or CHCHD2) is a bi-organellar (mitochondrial and nuclear) protein that is reduced in \u223c70% 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\n                    <jats:sup>mt<\/jats:sup>\n                    through regulation of the ATF5 transcription factor. Overexpression of MNRR1 in \u223c70% 3243G cybrid cells induces the UPR\n                    <jats:sup>mt<\/jats:sup>\n                    , autophagy, and mitochondrial biogenesis and restores mitochondrial respiratory function; furthermore, the proportion of wild-type mtDNA increases. 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