Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy

Author:

Chella Krishnan Karthickeyan1ORCID,El Hachem Elie-Julien2ORCID,Keller Mark P3,Patel Sanjeet G4,Carroll Luke5,Vegas Alexis Diaz5,Gerdes Gyuricza Isabela6,Light Christine7,Cao Yang8,Pan Calvin8,Kaczor-Urbanowicz Karolina Elżbieta910,Shravah Varun11,Anum Diana12,Pellegrini Matteo10,Lee Chi Fung713,Seldin Marcus M1415ORCID,Rosenthal Nadia A6,Churchill Gary A6ORCID,Attie Alan D3,Parker Benjamin16,James David E5ORCID,Lusis Aldons J81718

Affiliation:

1. Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine

2. Department of Integrative Biology and Physiology, Field Systems Biology, Sciences Sorbonne Université

3. Biochemistry Department, University of Wisconsin-Madison

4. Department of Surgery/Division of Cardiac Surgery, University of Southern California Keck School of Medicine

5. Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney

6. Jackson Laboratory

7. Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation

8. Department of Medicine/Division of Cardiology, University of California, Los Angeles

9. Division of Oral Biology and Medicine, UCLA School of Dentistry

10. UCLA Institute for Quantitative and Computational Biosciences

11. Department of Chemistry, University of California

12. Department of Integrative Biology and Physiology, University of California

13. Department of Physiology, University of Oklahoma Health Sciences Center

14. Center for Epigenetics and Metabolism

15. Department of Biological Chemistry, University of California

16. Department of Anatomy and Physiology, University of Melbourne

17. Department of Human Genetics, University of California

18. Department of Microbiology, Immunology and Molecular Genetics, University of California

Abstract

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.

Funder

National Institutes of Health

U.S. Department of Defense

Wisconsin Alumni Research Foundation

National Health and Medical Research Council

Systems Biology Association fellowship

Foundation Sorbonne fellowship

French Minister and Master BIP

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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