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JMG, Animals, Mice, Cardiomegaly, DNA, Mitochondrial, Electron Transport Complex I, Heart Failure, Mice, Inbred Strains, Mitochondria, Mitochondrial Proteins, Proteome

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Elife. 2023;12.







This work was supported by NIH grants DK120342, HL148577 and HL147883 (AJL) and DOD grant W81XWH2110115 (AJL); R00DK120875 (KCK); R00HL138193 (MMS); R01DK101573, R01DK102948, and RC2DK125961 (ADA); Wisconsin Alumni Research Foundation (MPK); National Health and Medical Research Council of Australia (NHMRC) grants and fellowships (DEJ and BLP); Systems Biology Asso- ciation fellowship, Foundation Sorbonne fellowship, French Minister, and Master BIP (EJEH). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.


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 trans-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, 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). 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 Lrpprc 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 trans to influence tissue-specific mitochondrial functions and contribute to heart hypertrophy, eluci- dating mechanisms that may underlie genetic susceptibility to heart failure in human populations.


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