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.
Reviewing Editor
- Richard J Youle, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States
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.
Version history
- Received: August 8, 2018
- Accepted: September 27, 2018
- Accepted Manuscript published: October 3, 2018 (version 1)
- Version of Record published: November 13, 2018 (version 2)
- Version of Record updated: November 15, 2018 (version 3)
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
-
- 3,364
- views
-
- 358
- downloads
-
- 15
- 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
- Chromosomes and Gene Expression
Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.
-
- Cell Biology
High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.
