Bid maintains mitochondrial cristae structure and function and protects against cardiac disease in an integrative genomics study.
Elife
; 72018 10 03.
Article
in En
| MEDLINE
| ID: mdl-30281024
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Genomics
/
BH3 Interacting Domain Death Agonist Protein
/
Heart Diseases
/
Mitochondria
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Elife
Year:
2018
Document type:
Article
Affiliation country:
Estados Unidos