| First Author | McManus MJ | Year | 2019 |
| Journal | Cell Metab | Volume | 29 |
| Issue | 1 | Pages | 78-90.e5 |
| PubMed ID | 30174309 | Mgi Jnum | J:271905 |
| Mgi Id | MGI:6282286 | Doi | 10.1016/j.cmet.2018.08.002 |
| Citation | McManus MJ, et al. (2019) Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy. Cell Metab 29(1):78-90.e5 |
| abstractText | Nuclear-encoded mutations causing metabolic and degenerative diseases have highly variable expressivity. Patients sharing the homozygous mutation (c.523delC) in the adenine nucleotide translocator 1 gene (SLC25A4, ANT1) develop cardiomyopathy that varies from slowly progressive to fulminant. This variability correlates with the mitochondrial DNA (mtDNA) lineage. To confirm that mtDNA variants can modulate the expressivity of nuclear DNA (nDNA)-encoded diseases, we combined in mice the nDNA Slc25a4(-/-) null mutation with a homoplasmic mtDNA ND6(P25L) or COI(V421A) variant. The ND6(P25L) variant significantly increased the severity of cardiomyopathy while the COI(V421A) variant was phenotypically neutral. The adverse Slc25a4(-/-) and ND6(P25L) combination was associated with impaired mitochondrial complex I activity, increased oxidative damage, decreased l-Opa1, altered mitochondrial morphology, sensitization of the mitochondrial permeability transition pore, augmented somatic mtDNA mutation levels, and shortened lifespan. The strikingly different phenotypic effects of these mild mtDNA variants demonstrate that mtDNA can be an important modulator of autosomal disease. |
