Sandra Zinkel
Assistant Professor of Medicine
Last active: 3/26/2019

Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.

Salisbury-Ruf CT, Bertram CC, Vergeade A, Lark DS, Shi Q, Heberling ML, Fortune NL, Okoye GD, Jerome WG, Wells QS, Fessel J, Moslehi J, Chen H, Roberts LJ, Boutaud O, Gamazon ER, Zinkel SS
Elife. 2018 7

PMID: 30281024 · PMCID: PMC6234033 · DOI:10.7554/eLife.40907

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. 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, Bid, associates with MI predisposition. Furthermore, Bid but not Bid associates with Mcl-1, 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.

© 2018, Salisbury-Ruf et al.

MeSH Terms (27)

Animals Apoptosis Beclin-1 BH3 Interacting Domain Death Agonist Protein Cell Respiration Fibrosis Gene Expression Regulation Genome-Wide Association Study Genomics Genomics Heart Diseases Heart Ventricles Humans Mice, Inbred C57BL Mitochondria Mitochondrial Proton-Translocating ATPases Mutation Myeloid Progenitor Cells Myocardial Infarction Myocytes, Cardiac Polymorphism, Single Nucleotide Protein Multimerization Protein Structure, Secondary Protein Subunits Reactive Oxygen Species Reproducibility of Results Up-Regulation

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