MNRR1 (CHCHD2) is a bi-organellar regulator of mitochondrial function that directly activates cytochrome c oxidase in the mitochondria and functions in the nucleus as a transcriptional activator for hundreds of genes. Since MNRR1 depletion contains features of a mitochondrial disease phenotype, we evaluated the effects of forced expression of MNRR1 on the mitochondrial disease MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome. MELAS is a multisystem encephalomyopathy disorder that can result from a heteroplasmic mutation in the mitochondrial DNA (mtDNA; m.3243A > G) at heteroplasmy levels of ∼50 to 90%. Since cybrid cell lines with 73% m.3243A > G heteroplasmy (DW7) display a significant reduction in MNRR1 levels compared to the wild type (0% heteroplasmy) (CL9), we evaluated the effects of MNRR1 levels on mitochondrial functioning. Overexpression of MNRR1 in DW7 cells induces the mitochondrial unfolded protein response (UPR^mt), autophagy, and mitochondrial biogenesis, thereby rescuing the mitochondrial phenotype. It does so primarily as a transcription activator, revealing this function to be a potential therapeutic target. The role of MNRR1 in stimulating UPR^mt, which is blunted in MELAS cells, was surprising and further investigation uncovered that under conditions of stress the import of MNRR1 into the mitochondria was blocked, allowing the protein to accumulate in the nucleus to enhance its transcription function. In the mammalian system, ATF5, has been identified as a mediator of UPR^mt. MNRR1 knockout cells display an ∼40% reduction in the protein levels of ATF5, suggesting that MNRR1 plays an important role upstream of this known mediator of UPR^mt.

MNRR1（CHCHD2）是线粒体功能的双细胞器调节剂，可直接激活细胞色素c线粒体中的氧化酶并在细胞核中起数百种基因的转录激活剂的作用。由于MNRR1耗竭包含线粒体疾病表型的特征，因此我们评估了MNRR1的强制表达对线粒体疾病MELAS（线粒体脑病，乳酸性酸中毒和中风样发作）综合征的影响。MELAS是一种多系统性脑病，可能是由线粒体DNA的异质性突变（mtDNA； m.3243A> G）导致，异质性水平约为50％至90％。由于具有73％m.3243A> G异质性（DW7）的杂交细胞系与野生型（0％异质性）（CL9）相比，MNRR1水平显着降低，因此我们评估了MNRR1水平对线粒体功能的影响。^mt），自噬和线粒体生物发生，从而挽救线粒体表型。它主要是作为转录激活因子来发挥作用，表明该功能是潜在的治疗靶标。令人惊讶的是，MNRR1在刺激在MELAS细胞中变弱的UPR ^mt中的作用令人惊讶，进一步的研究发现，在压力条件下，MNRR1进入线粒体的输入被阻断，从而使该蛋白积聚在细胞核中以增强其转录功能。 。在哺乳动物系统中，ATF5被确定为UPR ^mt的介体。MNRR1敲除细胞的ATF5蛋白质水平降低了约40％，这表明MNRR1在UPR ^mt的这种已知介体的上游起着重要作用。