Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, United States.
Department of Integrative Biology and Physiology, Field Systems Biology, Sciences Sorbonne Université, Paris, France.
Elife. 2023 Jun 5;12:e82619. doi: 10.7554/eLife.82619.
Mitochondria play an important role in both normal heart function and disease etiology. We report analysis of common genetic variations contributing to mitochondrial and heart functions using an integrative proteomics approach in a panel of inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP). We performed a whole heart proteome study in the HMDP (72 strains, n=2-3 mice) and retrieved 848 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their relative abundance levels revealed three -acting genetic loci on chromosomes (chr) 7, 13 and 17 that regulate distinct classes of mitochondrial proteins as well as cardiac hypertrophy. DAVID enrichment analyses of genes regulated by each of the loci revealed that the chr13 locus was highly enriched for complex-I proteins (24 proteins, =2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, =3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, =6.9E-05). Follow-up high resolution regional mapping identified NDUFS4, LRPPRC and COQ7 as the candidate genes for chr13, chr17 and chr7 loci, respectively, and both experimental and statistical analyses supported their causal roles. Furthermore, a large cohort of Diversity Outbred mice was used to corroborate gene as a driver of mitochondrial DNA (mtDNA)-encoded gene regulation, and to show that the chr17 locus is specific to heart. Variations in all three loci were associated with heart mass in at least one of two independent heart stress models, namely, isoproterenol-induced heart failure and diet-induced obesity. These findings suggest that common variations in certain mitochondrial proteins can act in to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.
线粒体在正常心脏功能和疾病发病机制中都起着重要作用。我们报告了使用整合蛋白质组学方法在称为杂种鼠多样性面板（HMDP）的一组近交系小鼠中分析导致线粒体和心脏功能的常见遗传变异的结果。我们在 HMDP 中进行了全心脏蛋白质组研究（72 个品系，n=2-3 只小鼠），并检索到 848 种线粒体蛋白（在≥50 个品系中进行了定量）。对其相对丰度水平进行高分辨率关联作图显示，三个染色体（chr）7、13 和 17 上的遗传位点可调节不同类别的线粒体蛋白和心脏肥大。受每个位点调节的基因的 DAVID 富集分析显示，chr13 位点高度富含复合物 I 蛋白（24 种蛋白，=2.2E-61），chr17 位点富含线粒体核糖核蛋白复合物（17 种蛋白，=3.1E-25），chr7 位点富含泛醌生物合成（3 种蛋白，=6.9E-05）。后续的高分辨率区域作图确定 NDUFS4、LRPPRC 和 COQ7 分别为 chr13、chr17 和 chr7 位点的候选基因，实验和统计分析均支持它们的因果作用。此外，大量的多样性杂交鼠群体被用于证实基因是线粒体 DNA（mtDNA）编码基因调控的驱动因素，并表明 chr17 位点是心脏特有的。在至少一种两种独立的心脏应激模型（即异丙肾上腺素诱导的心力衰竭和饮食诱导的肥胖）中，这三个位点的变异与心脏质量有关。这些发现表明，某些线粒体蛋白的常见变异可以共同作用，影响组织特异性线粒体功能，并导致心脏肥大，阐明了可能导致人类心力衰竭遗传易感性的机制。
