Abstract
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.
Highlights
The critical function for Bcl-2 family proteins during apoptosis transpires at the mitochondria and involves remodeling of both the inner and outer mitochondrial membranes to mobilize cytochrome c and release it into the cytosol
In addition to MCL-1, we find that MTX1 (Metaxin1), a mitochondrial protein transporter that associates with the mitochondrial contact site and cristae reorganizing complex (MICOS) complex (Guarani et al, 2015), has reduced genetically determined expression significantly associated with myocardial infarction (MI) (p=1.93Â10À5)
Our results add to the body of literature implicating a role for the Bcl-2 family in mitochondrial membrane remodeling in the absence of apoptosis
Summary
The critical function for Bcl-2 family proteins during apoptosis transpires at the mitochondria and involves remodeling of both the inner and outer mitochondrial membranes to mobilize cytochrome c and release it into the cytosol. Human genetics analysis using PrediXcan reveals decreased BID gene expression associated with MI and BID exome level variation identifies coding SNP M148T, which is directly linked to Bid’s mitochondrial function. This SNP fails to restore cristae structure, respiration, and association with Mcl-1Matrix. We shed light on the regulation of mitochondrial cristae and oxidative phosphorylation and reveal an important role for Bid’s alpha-helix-6 in regulation of mitochondrial function under homeostatic conditions This approach provides a model for elucidating previously unrecognized proteins that impact complex genetic diseases
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