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Sex differences in heart mitochondria regulate diastolic dysfunction

Author

Listed:
  • Yang Cao

    (University of California)

  • Laurent Vergnes

    (Metabolism Theme, David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA)

  • Yu-Chen Wang

    (University of California)

  • Calvin Pan

    (University of California)

  • Karthickeyan Chella Krishnan

    (University of California
    University of Cincinnati College of Medicine)

  • Timothy M. Moore

    (University of California)

  • Manuel Rosa-Garrido

    (University of Alabama at Birmingham)

  • Todd H. Kimball

    (David Geffen School of Medicine at UCLA)

  • Zhiqiang Zhou

    (University of California)

  • Sarada Charugundla

    (University of California)

  • Christoph D. Rau

    (David Geffen School of Medicine at UCLA)

  • Marcus M. Seldin

    (University of California)

  • Jessica Wang

    (University of California)

  • Yibin Wang

    (David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA)

  • Thomas M. Vondriska

    (David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA)

  • Karen Reue

    (Metabolism Theme, David Geffen School of Medicine at UCLA
    David Geffen School of Medicine at UCLA
    Molecular Biology Institute at UCLA)

  • Aldons J. Lusis

    (University of California
    David Geffen School of Medicine at UCLA
    University of California)

Abstract

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

Suggested Citation

  • Yang Cao & Laurent Vergnes & Yu-Chen Wang & Calvin Pan & Karthickeyan Chella Krishnan & Timothy M. Moore & Manuel Rosa-Garrido & Todd H. Kimball & Zhiqiang Zhou & Sarada Charugundla & Christoph D. Rau, 2022. "Sex differences in heart mitochondria regulate diastolic dysfunction," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31544-5
    DOI: 10.1038/s41467-022-31544-5
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    References listed on IDEAS

    as
    1. Pablo Cordero & Victoria N. Parikh & Elizabeth T. Chin & Ayca Erbilgin & Michael J. Gloudemans & Ching Shang & Yong Huang & Alex C. Chang & Kevin S. Smith & Frederick Dewey & Kathia Zaleta & Michael M, 2019. "Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    2. Peng Yue & Siyuan Jing & Lei Liu & Fan Ma & Yi Zhang & Chuan Wang & Hongyu Duan & Kaiyu Zhou & Yimin Hua & Gang Wu & Yifei Li, 2018. "Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis," PLOS ONE, Public Library of Science, vol. 13(11), pages 1-15, November.
    3. Gabriele G. Schiattarella & Francisco Altamirano & Dan Tong & Kristin M. French & Elisa Villalobos & Soo Young Kim & Xiang Luo & Nan Jiang & Herman I. May & Zhao V. Wang & Theodore M. Hill & Pradeep P, 2019. "Nitrosative stress drives heart failure with preserved ejection fraction," Nature, Nature, vol. 568(7752), pages 351-356, April.
    4. Gabriele G. Schiattarella & Francisco Altamirano & Soo Young Kim & Dan Tong & Anwarul Ferdous & Hande Piristine & Subhajit Dasgupta & Xuliang Wang & Kristin M. French & Elisa Villalobos & Stephen B. S, 2021. "Xbp1s-FoxO1 axis governs lipid accumulation and contractile performance in heart failure with preserved ejection fraction," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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    Cited by:

    1. Niranjana Natarajan & Jonathan Florentin & Ebin Johny & Hanxi Xiao & Scott Patrick O’Neil & Liqun Lei & Jixing Shen & Lee Ohayon & Aaron R. Johnson & Krithika Rao & Xiaoyun Li & Yanwu Zhao & Yingze Zh, 2024. "Aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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