线粒体 DNA 变异决定了导致心肌病的核 DNA 突变的表达和进展

Mitochondrial DNA Variation Dictates Expressivity and Progression of Nuclear DNA Mutations Causing Cardiomyopathy

Keywords：mitochondrial-nuclear interaction,mitochondrial DNA,adenine nucleotide translocator,complex I,complex IV,OPA1,F1Fo-ATPase,mtDNA instability,
cardiomyopathy,aging

关键词：线粒体-核相互作用、线粒体 DNA、腺嘌呤核苷酸转运蛋白、复合物 I、复合物 IV、OPA1、F1Fo-ATP 酶、mtDNA 不稳定性、心肌病、衰老
作者：Meagan J. McManus,Martin Picard, Hsiao-Wen Chen, Hans J. De Haas,Prasanth Potluri, Jeremy Leipzig,
Atif Towheed, Alessia Angelin1 Partho Sengupta,Ryan M. Morrow, Brett A. Kauffman, Marc Vermulst,Jagat Narula, and Douglas C. Wallace1
出版期刊：《Cell Metabolism》 2019/1/8

Abstract：

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 ND6P25L or COIV421A variant. The ND6P25L variant significantly increased the severity of cardiomyopathy while the COIV421A variant was phenotypically neutral. The adverse Slc25a4-/- and ND6P25L 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.

文章摘要：

导致代谢和退行性疾病的核编码突变具有高度可变的表达能力。腺嘌呤核苷酸转运蛋白 1 基因 (SLC25A4, ANT1) 中存在纯合突变 (c.523delC) 的患者会发展为从缓慢进展到暴发性的心肌病。这种变异性与线粒体 DNA (mtDNA) 谱系相关。为了证实 mtDNA 变体可以调节核 DNA (nDNA) 编码疾病的表达能力，我们在小鼠中将 nDNA Slc25a4-/- 无效突变与同质 mtDNA ND6P25L 或 COIV421A 变体相结合。 ND6P25L 变体显着增加了心肌病的严重程度，而 COIV421A 变体在表型上呈中性。不利的 Slc25a4-/- 和 ND6P25L 组合与线粒体复合物 I 活性受损、氧化损伤增加、l-Opa1 减少、线粒体形态改变、线粒体通透性转换孔致敏、体细胞 mtDNA 突变水平增加和寿命缩短有关。这些温和的 mtDNA 变体显着不同的表型效应表明 mtDNA 可以是常染色体疾病的重要调节剂。

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