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Mitochondrial Nuclear Retrograde Regulator 1 (MNRR1) rescues the cellular phenotype of MELAS by inducing homeostatic mechanisms
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| Zeitschriftentitel: | Proceedings of the National Academy of Sciences |
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| Personen und Körperschaften: | , , , , , , |
| In: | Proceedings of the National Academy of Sciences, 117, 2020, 50, S. 32056-32065 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Proceedings of the National Academy of Sciences
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| Schlagwörter: |
| Zusammenfassung: | <jats:title>Significance</jats:title> <jats:p> 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 <jats:sup>mt</jats:sup> ) 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 <jats:sup>mt</jats:sup> through regulation of the ATF5 transcription factor. Overexpression of MNRR1 in ∼70% 3243G cybrid cells induces the UPR <jats:sup>mt</jats:sup> , 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. </jats:p> |
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| Umfang: | 32056-32065 |
| ISSN: |
0027-8424
1091-6490 |
| DOI: | 10.1073/pnas.2005877117 |