Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy
| Title: | Genetic architecture of heart mitochondrial proteome influencing cardiac hypertrophy |
|---|---|
| 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 |
| Source: | eLife, Vol 12 (2023) |
| Publisher Information: | eLife Sciences Publications Ltd, 2023. |
| Publication Year: | 2023 |
| Collection: | LCC:Medicine LCC:Science LCC:Biology (General) |
| Subject Terms: | proteomics, metabolic syndrome, genetic, association studies, mitochondria, hypertrophy, heart failure, Medicine, Science, Biology (General), QH301-705.5 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2050-084X |
| Relation: | https://elifesciences.org/articles/82619; https://doaj.org/toc/2050-084X |
| DOI: | 10.7554/eLife.82619 |
| Access URL: | https://doaj.org/article/2a1b6fe7048b41d5bd20badbfb9d149f |
| Accession Number: | edsdoj.2a1b6fe7048b41d5bd20badbfb9d149f |
| Database: | Directory of Open Access Journals |
| ISSN: | 2050084X |
|---|---|
| DOI: | 10.7554/eLife.82619 |
| Published in: | eLife |
| Language: | English |