Genetic Architecture Of Heart Mitochondrial Proteome Influencing Cardiac Hypertrophy

Our lab studies how natural genetic variations affect common diseases using a mouse population called hybrid mouse diversity panel (HMDP). In this study, we have explored the genetic regulation of mitochondrial pathways and their contribution to heart function using an integrative proteomics approach. We first performed a whole heart proteomic analysis in the HMDP (72 strains, n=2-3 mice) and surveyed mitochondrial localization using MitoCarta2.0. We retrieved 840 of these proteins (quantified in ≥50 strains) and performed high-resolution association mapping on their respective abundance levels to the HMDP genotypes. Our analyses identified three 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. All three are associated with heart mass in two independent heart stress models, namely, isoproterenol (ISO)-induced heart failure and diet-induced obesity (DIO) models. Next, 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) and identified five modules. Eigengenes, representing the first principal component of two of these modules (Brown and Green), mapped to the same regions as the chr13 and chr17 loci, respectively. DAVID enrichment analyses revealed that the Brown module (72 proteins, 96% overlap with chr13) was highly enriched for complex-I proteins (35 proteins, P = 8.8E-74) and the Green module (44 proteins, 73% overlap with chr17) for mitochondrial ribosomal proteins (25 proteins, P = 1.3E-53). The proteins in the chr7 locus were found primarily in the Turquoise module (393 proteins, 81% overlap) but this module was not enriched for any single mitochondrial protein complex. In summary, we now report the identification of three genetic loci that control distinct classes of mitochondrial proteins as well as heart hypertrophy. Our results provide strong support for a role of the mitochondrial proteome in heart pathophysiology.