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

Autor:	Salisbury-Ruf CT; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States., Bertram CC; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States., Vergeade A; Department of Pharmacology, Vanderbilt University, Nashville, United States., Lark DS; Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States., Shi Q; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States., Heberling ML; Department of Biological Sciences, Vanderbilt University, Nashville, United States., Fortune NL; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States., Okoye GD; Division of Cardiovascular Medicine and Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, United States., Jerome WG; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, United States., Wells QS; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States., Fessel J; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States., Moslehi J; Division of Cardiovascular Medicine and Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, United States., Chen H; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States., Roberts LJ 2nd; Department of Pharmacology, Vanderbilt University, Nashville, United States.; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States., Boutaud O; Department of Pharmacology, Vanderbilt University, Nashville, United States., Gamazon ER; Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, United States.; Clare Hall, University of Cambridge, Cambridge, United Kingdom., Zinkel SS; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States.; Department of Medicine, Vanderbilt University Medical Center, Nashville, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2018 Oct 03; Vol. 7. Date of Electronic Publication: 2018 Oct 03.
DOI:	10.7554/eLife.40907
Abstrakt:	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, Bid M148T , associates with MI predisposition. Furthermore, Bid but not Bid M148T associates with Mcl-1 Matrix , 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. Competing Interests: CS, CB, AV, DL, QS, MH, NF, GO, WJ, QW, JF, JM, HC, LR, OB, EG, SZ No competing interests declared (© 2018, Salisbury-Ruf et al.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu