Genetic Architecture of Heart Mitochondrial Proteome influencing Cardiac Hypertrophy

Mitochondria play a key role in the normal function of the heart as well as in the pathogenesis of diseases. 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 proteomic analysis in the HMDP (72 strains, n=2-3 mice) and retrieved 840 mitochondrial proteins (quantified in ≥50 strains). High-resolution association mapping on their respective abundance levels identified three trans-acting genetic loci, located on chromosome (chr) 7, chr13 and chr17, that control distinct classes of mitochondrial proteins as well as heart hypertrophy. 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. Variations of all three were associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. To identify the aspects of mitochondrial metabolism regulated by these loci, we constructed co-expression protein networks using weighted gene co-expression network analysis (WGCNA). 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, P = 2.2E-61), the chr17 locus for mitochondrial ribonucleoprotein complex (17 proteins, P = 3.1E-25) and the chr7 locus for ubiquinone biosynthesis (3 proteins, P = 6.9E-05). These results indicate that common variations of certain mitochondrial proteins can act in trans to influence mitochondrial functions and contribute to heart hypertrophy, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations. ### Competing Interest Statement The authors have declared no competing interest. * HMDP : hybrid mouse diversity panel WGCNA : weighted gene co-expression network analysis pQTL/s : protein quantitative trait locus/loci ISO : isoproterenol DIO : diet-induced obesity miR : microRNA NDUFS4 : NADH-ubiquinone oxidoreductase subunit S4 or NADH dehydrogenase [ubiquinone] iron-sulfur protein 4, mitochondrial NRVM : neonatal rat ventricular myocytes LRPPRC : leucine-rich pentatricopeptide repeat motif-containing protein SLIRP : SRA stem-loop interacting RNA binding protein COQ7 : coenzyme Q7, hydroxylase or mitochondrial 5-demethoxyubiquinone hydroxylase CoQ : coenzyme Q or ubiquinone