Sex differences in heart mitochondria regulate diastolic dysfunction

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, Marcus M. Seldin, Jessica Wang, Yibin Wang, Thomas M. Vondriska, Karen Reue and Aldons J. Lusis ()
Additional contact information
Yang Cao: University of California
Laurent Vergnes: Metabolism Theme, David Geffen School of Medicine at UCLA
Yu-Chen Wang: University of California
Calvin Pan: University of California
Karthickeyan Chella Krishnan: University of California
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
Thomas M. Vondriska: David Geffen School of Medicine at UCLA
Karen Reue: Metabolism Theme, David Geffen School of Medicine at UCLA
Aldons J. Lusis: University of California

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31544-5

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