Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy

Karthickeyan Chella Krishnan; Elie-Julien El Hachem; Mark P Keller; Sanjeet G Patel; Luke Carroll; Alexis Diaz Vegas; Isabela Gerdes Gyuricza; Christine Light; Yang Cao; Calvin Pan; Karolina Elżbieta Kaczor-Urbanowicz; Varun Shravah; Diana Anum; Matteo Pellegrini; Chi Fung Lee; Marcus M Seldin; Nadia A Rosenthal; Gary A Churchill; Alan D Attie; Benjamin Parker; David E James; Aldons J Lusis

doi:10.7554/eLife.82619

Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy

Elife. 2023 Jun 5:12:e82619. doi: 10.7554/eLife.82619.

Authors

Karthickeyan Chella Krishnan¹, Elie-Julien El Hachem², Mark P Keller³, Sanjeet G Patel⁴, Luke Carroll⁵, Alexis Diaz Vegas⁵, Isabela Gerdes Gyuricza⁶, Christine Light⁷, Yang Cao⁸, Calvin Pan⁸, Karolina Elżbieta Kaczor-Urbanowicz^{9

10}, Varun Shravah¹¹, Diana Anum¹², Matteo Pellegrini¹⁰, Chi Fung Lee^{7

13}, Marcus M Seldin^{14

15}, Nadia A Rosenthal⁶, Gary A Churchill⁶, Alan D Attie³, Benjamin Parker¹⁶, David E James⁵, Aldons J Lusis^{8

17

18}

Affiliations

¹ Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, United States.
² Department of Integrative Biology and Physiology, Field Systems Biology, Sciences Sorbonne Université, Paris, France.
³ Biochemistry Department, University of Wisconsin-Madison, Madison, United States.
⁴ Department of Surgery/Division of Cardiac Surgery, University of Southern California Keck School of Medicine, Los Angeles, United States.
⁵ Metabolic Systems Biology Laboratory, Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia.
⁶ Jackson Laboratory, Bar Harbor, United States.
⁷ Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, United States.
⁸ Department of Medicine/Division of Cardiology, University of California, Los Angeles, Los Angeles, United States.
⁹ Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, United States.
¹⁰ UCLA Institute for Quantitative and Computational Biosciences, Los Angeles, United States.
¹¹ Department of Chemistry, University of California, Los Angeles, United States.
¹² Department of Integrative Biology and Physiology, University of California, Los Angeles, United States.
¹³ Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, United States.
¹⁴ Center for Epigenetics and Metabolism, Irvine, United States.
¹⁵ Department of Biological Chemistry, University of California, Irvine, United States.
¹⁶ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia.
¹⁷ Department of Human Genetics, University of California, Los Angeles, United States.
¹⁸ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, United States.

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.

Keywords: computational biology; genetic, association studies; genetics; genomics; heart failure; hypertrophy; metabolic syndrome; mitochondria; mouse; proteomics; systems biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cardiomegaly / genetics
DNA, Mitochondrial / metabolism
Electron Transport Complex I / metabolism
Heart Failure* / genetics
Heart Failure* / metabolism
Mice
Mice, Inbred Strains
Mitochondria / metabolism
Mitochondrial Proteins / genetics
Mitochondrial Proteins / metabolism
Proteome* / metabolism

Substances

DNA, Mitochondrial
Electron Transport Complex I
Mitochondrial Proteins
Ndufs4 protein, mouse
Proteome

Associated data

GEO/GSE207142
GEO/GSE194198

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding