Department of Integrative Biology and Physiology, Field Systems Biology, Sciences Sorbonne Université, Paris, France
Mark P Keller
Biochemistry Department, University of Wisconsin-Madison, Madison, United States
Sanjeet G Patel
Department of Surgery/Division of Cardiac Surgery, University of Southern California Keck School of Medicine, Los Angeles, United States
Luke Carroll
Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Alexis Diaz Vegas
Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Isabela Gerdes Gyuricza
Jackson Laboratory, Bar Harbor, United States
Christine Light
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States
Yang Cao
Department of Medicine/Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
Calvin Pan
Department of Medicine/Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
Karolina Elżbieta Kaczor-Urbanowicz
Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, United States; UCLA Institute for Quantitative and Computational Biosciences, Los Angeles, United States
Varun Shravah
Department of Chemistry, University of California, Los Angeles, United States
Diana Anum
Department of Integrative Biology and Physiology, University of California, Los Angeles, United States
Matteo Pellegrini
UCLA Institute for Quantitative and Computational Biosciences, Los Angeles, United States
Chi Fung Lee
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States; Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States
Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Aldons J Lusis
Department of Medicine/Division of Cardiology, University of California, Los Angeles, Los Angeles, United States; Department of Human Genetics, University of California, Los Angeles, United States; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, United States
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, elucidating mechanisms that may underlie genetic susceptibility to heart failure in human populations.
