Bid maintains mitochondrial cristae structure and protects against cardiac disease in an integrative genomics study
- Vanderbilt University, United States
- Vanderbilt University Medical Center, United States
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.
Data availability
The authors declare that all relevant data are available within the article and its supplementary information files. Publicly available data on coronary artery disease / myocardial infarction have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.GTEx Consortium (v6p) transcriptome/genotype data is available through the GTEx portal (htt://www.gtexportal.org) and through dpGap (GTEx Consortium, Nature 2017). Due to the GTEx Consortium's donor consent agreement, the raw data and attributes which may be used to identify the participants are not publicly available. Requests for access can be made through the dbGaP: https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000424.v6.p1 and are assessed bu a Data Access Committee (National Human Genome Research Institute; nhgridac@mail.nih.gov). The summary statistics results for eQTL data (v6p) are available through the GTEx portal: https://gtexportal.org/home/datasets.Investigators may obtain access to UK Biobank data through an application process: http://www.ukbiobank.ac.uk/register-apply/. The registration is then reviewed by the Access Management Team of the UK Biobank. Genome-wide association studies summary statistics results are publicly available: http://www.nealelab.is/blog/2017/7/19/rapid-gwas-of-thousands-of-phenotypes-for-337000-samples-in-the-uk-biobankModel definition files are described in Gamazon et al. 2015. Code for the following analyses is publicly available: PrediXcan: https://github.com/hakyimlab/PrediXcan S-PrediXcan: https://github.com/hakyimlab/MetaXcan
-
GTEx PortAvailable through request.
-
Genetic studies of body mass index yield new insights for obesity biologyData is publically available from: Genetic studies of body mass index yield new insights for obesity biology. 2015 doi: 0.1038/nature14177.
-
Systematic identification of trans eQTLs as putative drivers of known disease associationsData is publically available from: Systematic identification of trans eQTLs as putative drivers of known disease associations.2013. doi: 10.1038/ng.2756.
-
Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary DiseaseData is publically available at the New England Journal of Medicine. 2016. doi: 10.1056/NEJMoa1507652.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (1R01HL088347)
- Sandra S Zinkel
National Institute of Mental Health (R01 MH090937)
- Eric Gamazon
U.S. Department of Veterans Affairs (1I01BX002250)
- Sandra S Zinkel
National Institute of General Medical Sciences (2P01 GM015431)
- L Jackson Roberts II
National Institute of Mental Health (R01 MH101820)
- Eric Gamazon
American Heart Association (16POST299100001)
- Daniel S Lark
Francis Family Foundation
- Josh Fessel
National Institute of Diabetes and Digestive and Kidney Diseases (GRU2558)
- Daniel S Lark
National Heart, Lung, and Blood Institute (K08HL121174)
- Josh Fessel
National Heart, Lung, and Blood Institute (1 R01HL133559)
- Sandra S Zinkel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mice were housed and experiments performed with approval by the IACUC Protocol # M1600037, M1600220, M/14/231, and # V-17-001 of Vanderbilt University Medical Center and the Tennessee Valley VA in compliance with NIH guidelines.
Copyright
© 2018, Salisbury-Ruf et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,458
- views
-
- 365
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Bid maintains mitochondrial cristae structure and protects against cardiac disease in an integrative genomics study
eLife 7:e40907.
https://doi.org/10.7554/eLife.40907
Further reading
-
- Cell Biology
Multiple gut antimicrobial mechanisms are coordinated in space and time to efficiently fight foodborne pathogens. In Drosophila melanogaster, production of reactive oxygen species (ROS) and antimicrobial peptides (AMPs) together with intestinal cell renewal play a key role in eliminating gut microbes. A complementary mechanism would be to isolate and treat pathogenic bacteria while allowing colonization by commensals. Using real-time imaging to follow the fate of ingested bacteria, we demonstrate that while commensal Lactiplantibacillus plantarum freely circulate within the intestinal lumen, pathogenic strains such as Erwinia carotovora or Bacillus thuringiensis, are blocked in the anterior midgut where they are rapidly eliminated by antimicrobial peptides. This sequestration of pathogenic bacteria in the anterior midgut requires the Duox enzyme in enterocytes, and both TrpA1 and Dh31 in enteroendocrine cells. Supplementing larval food with hCGRP, the human homolog of Dh31, is sufficient to block the bacteria, suggesting the existence of a conserved mechanism. While the immune deficiency (IMD) pathway is essential for eliminating the trapped bacteria, it is dispensable for the blockage. Genetic manipulations impairing bacterial compartmentalization result in abnormal colonization of posterior midgut regions by pathogenic bacteria. Despite a functional IMD pathway, this ectopic colonization leads to bacterial proliferation and larval death, demonstrating the critical role of bacteria anterior sequestration in larval defense. Our study reveals a temporal orchestration during which pathogenic bacteria, but not innocuous, are confined in the anterior part of the midgut in which they are eliminated in an IMD-pathway-dependent manner.
-
- Cancer Biology
- Cell Biology
Understanding the cell cycle at the single-cell level is crucial for cellular biology and cancer research. While current methods using fluorescent markers have improved the study of adherent cells, non-adherent cells remain challenging. In this study, we addressed this gap by combining a specialized surface to enhance cell attachment, the FUCCI(CA)2 sensor, an automated image analysis pipeline, and a custom machine learning algorithm. This approach enabled precise measurement of cell cycle phase durations in non-adherent cells. This method was validated in acute myeloid leukemia cell lines NB4 and Kasumi-1, which have unique cell cycle characteristics, and we tested the impact of cell cycle-modulating drugs on NB4 cells. Our cell cycle analysis system, which is also compatible with adherent cells, is fully automated and freely available, providing detailed insights from hundreds of cells under various conditions. This report presents a valuable tool for advancing cancer research and drug development by enabling comprehensive, automated cell cycle analysis in both adherent and non-adherent cells.
