Bcl-2 family proteins reorganize mitochondrial membranes during apoptosis, to form pores and rearrange cristae. In vitro and in vivo analysis integrated with human genetics reveals a novel homeostatic mitochondrial function for Bcl-2 family protein Bid. Loss of full-length Bid results in apoptosis-independent, irregular cristae with decreased respiration. Bid-/- mice display stress-induced myocardial dysfunction and damage. A gene-based approach applied to a biobank, validated in two independent GWAS studies, reveals that decreased genetically determined BID expression associates with myocardial infarction (MI) susceptibility. Patients in the bottom 5% of the expression distribution exhibit >4 fold increased MI risk. Carrier status with nonsynonymous variation in Bid's membrane binding domain, BidM148T, associates with MI predisposition. Furthermore, Bid but not BidM148T associates with Mcl-1Matrix, previously implicated in cristae stability; decreased MCL-1 expression associates with MI. Our results identify a role for Bid in homeostatic mitochondrial cristae reorganization, that we link to human cardiac disease.
BH3 Interacting Domain Death Agonist Protein/metabolism , Genomics , Heart Diseases/genetics , Heart Diseases/prevention & control , Mitochondria/metabolism , Mitochondria/ultrastructure , Animals , Apoptosis , BH3 Interacting Domain Death Agonist Protein/chemistry , Beclin-1/metabolism , Cell Respiration , Fibrosis , Gene Expression Regulation , Genome-Wide Association Study , Heart Diseases/pathology , Heart Ventricles/pathology , Humans , Mice, Inbred C57BL , Mitochondrial Proton-Translocating ATPases , Mutation/genetics , Myeloid Progenitor Cells/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Myocytes, Cardiac/ultrastructure , Polymorphism, Single Nucleotide/genetics , Protein Multimerization , Protein Structure, Secondary , Protein Subunits/metabolism , Reactive Oxygen Species/metabolism , Reproducibility of Results , Up-Regulation
Haploinsufficiency of the melanocortin-4 receptor, the most common monogenetic obesity syndrome in humans, is associated with a reduction in autonomic tone, bradycardia, and incidence of obesity-associated hypertension. Thus, it has been assumed that melanocortin obesity syndrome may be protective with respect to obesity-associated cardiovascular disease. We show here that absence of the melanocortin-4 receptor (MC4R) in mice causes dilated cardiomyopathy, characterized by reduced contractility and increased left ventricular diameter. This cardiomyopathy is independent of obesity as weight matched diet induced obese mice do not display systolic dysfunction. Mc4r cardiomyopathy is characterized by ultrastructural changes in mitochondrial morphology and cardiomyocyte disorganization. Remarkably, testing of myocardial tissue from Mc4r-/- mice exhibited increased ADP stimulated respiratory capacity. However, this increase in respiration correlates with increased reactive oxygen species production - a canonical mediator of tissue damage. Together this study identifies MC4R deletion as a novel and potentially clinically important cause of heart failure.
Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Receptor, Melanocortin, Type 4/deficiency , Adenosine Diphosphate/metabolism , Animals , Cell Respiration/drug effects , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/ultrastructure , Myocardium/pathology , Myocytes, Cardiac/pathology , Reactive Oxygen Species/metabolism , Reactive Oxygen Species/toxicity
