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

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

The following previously published data sets were used
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    2. Peters MJ
    3. Esko T
    4. Yaghootkar H
    5. Schurmann C
    6. Kettunen J et al
    (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations
    Data is publically available from: Systematic identification of trans eQTLs as putative drivers of known disease associations.2013. doi: 10.1038/ng.2756.

Article and author information

Author details

  1. Christi T Salisbury-Ruf

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Clinton C Bertram

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Aurelia Vergeade

    Department of Pharmacology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniel S Lark

    Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiong Shi

    Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Marlene L Heberling

    Department of Biological Sciences, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Niki L Fortune

    Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. G Donald Okoye

    Division of Cardiovascular Medicine and Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1078-688X
  9. W Grey Jerome

    Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Quinn S Wells

    Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Josh Fessel

    Department of Medicine, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Javid Moslehi

    Division of Cardiovascular Medicine and Cardio-oncology Program, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Heidi Chen

    Department of Biostatistics, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. L Jackson Roberts II

    Department of Pharmacology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Olivier Boutaud

    Department of Pharmacology, Vanderbilt University, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Eric Gamazon

    Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, United States
    For correspondence
    Eric.gamazon@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
  17. Sandra S Zinkel

    Department of Cell and Developmental Biology, Vanderbilt University, Nashville, United States
    For correspondence
    sandra.zinkel@vanderbilt.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2818-9795

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.

Reviewing Editor

  1. Richard J Youle, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: August 8, 2018
  2. Accepted: September 27, 2018
  3. Accepted Manuscript published: October 3, 2018 (version 1)
  4. Version of Record published: November 13, 2018 (version 2)
  5. 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.

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  1. Christi T Salisbury-Ruf
  2. Clinton C Bertram
  3. Aurelia Vergeade
  4. Daniel S Lark
  5. Qiong Shi
  6. Marlene L Heberling
  7. Niki L Fortune
  8. G Donald Okoye
  9. W Grey Jerome
  10. Quinn S Wells
  11. Josh Fessel
  12. Javid Moslehi
  13. Heidi Chen
  14. L Jackson Roberts II
  15. Olivier Boutaud
  16. Eric Gamazon
  17. Sandra S Zinkel
(2018)
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

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