Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy
Year: 2023
Type: article
Abstract: ABSTRACT 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.
Source: eLife
DOI: 10.7554/elife.82619
Authors: 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
Institutions: University of Cincinnati, Sorbonne Université, University of Wisconsin–Madison, University of Southern California, The University of Sydney, Jackson Laboratory, Oklahoma Medical Research Foundation, University of California, Los Angeles, University of Oklahoma Health Sciences Center, University of California System, The University of Melbourne
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G1250855596, Systems genetics approach to inflammatory mechanisms in atherosclerosis, G2050201625, Investigating the sex-specific roles of PKLR and CHCHD6 in insulin resistance and NAFLD, G2916338668, SEX DIFFERENCES IN CARDIAC FIBROSIS AND HYPERTROPHY, Establishing mechanistic links between the gut microbiome and atherosclerosis, A strategy for discovery of endocrine interactions, G9000033739, G9000070643, G9000249210, Systems Genetics Dissection of Non-alcoholic Steatohepatitis, Genetic Control of Metabolic Flux in Response to Diet
OpenAlex ID: W4379470926