Mitochondrial heterogeneity across cardiac cell types in heart failure with preserved ejection fraction
4 affiliations
- 1Department of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- 2Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA
- 3Department of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA; Corresponding author. Department of Cardiovascular Medicine Wake Forest University School of Medicine, Medical Center Blvd. NRC/Commons Building: Office 219, Winston-Salem, NC, 27157, USA.
- 4Department of Internal Medicine, Section of Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, 27157, USA; Corresponding author. Section of Gerontology and Geriatric Medicine Department of Internal Medicine Wake Forest University School of Medicine, Medical Center Blvd. NRC/Commons Building: Office 220, Winston-Salem, NC, 27157, USA.
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous and increasingly prevalent syndrome for which effective disease-modifying therapies remain limited, in part because its multicellular pathophysiology remains incompletely understood. Mitochondrial dysfunction has emerged as an important contributor to HFpEF, yet most studies have examined mitochondrial abnormalities within individual cell types rather than as part of an integrated cardiac microenvironment. This review discusses evidence that cell-type-specific mitochondrial alterations in cardiomyocytes, fibroblasts, and endothelial cells may interact through redox, metabolic, and paracrine signaling to promote diastolic dysfunction, myocardial stiffening, and impaired energetic reserve. In cardiomyocytes, disrupted mitochondrial calcium ( m Ca 2+ ) handling and redox imbalance uncouple ATP production from energetic demand, contributing to Ca 2+ overload, mitochondrial reactive oxygen species (mtROS) generation, and impaired relaxation. In fibroblasts, mitochondrial and metabolic reprogramming support profibrotic activation and extracellular matrix (ECM) deposition. In endothelial cells, mitochondrial dysfunction reduces nitric oxide bioavailability, enhances oxidative stress, and contributes to microvascular dysfunction. Together, these cell-type-specific mitochondrial abnormalities may converge on a redox–calcium–energetics axis that helps explain the dissociation between preserved systolic function and impaired diastolic performance in HFpEF. We further highlight mitochondrial heterogeneity and intercellular crosstalk as potential determinants of disease progression and discuss emerging therapeutic strategies targeting mitochondrial pathways as a rationale for precision approaches in HFpEF.
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BibTeX
@article{sinha2026mitochondrial,
title = {{Mitochondrial heterogeneity across cardiac cell types in heart failure with preserved ejection fraction}},
author = {Anupriya Sinha and Devin Kolmetzky and Dhanendra Tomar and Pooja Jadiya},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104402},
url = {https://doi.org/10.1016/j.redox.2026.104402},
note = {CC BY},
}
RIS
TY - JOUR
TI - Mitochondrial heterogeneity across cardiac cell types in heart failure with preserved ejection fraction
AU - Anupriya Sinha
AU - Devin Kolmetzky
AU - Dhanendra Tomar
AU - Pooja Jadiya
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104402
UR - https://doi.org/10.1016/j.redox.2026.104402
AB - Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous and increasingly prevalent syndrome for which effective disease-modifying therapies remain limited, in part because its multicellular pathophysiology remains incompletely understood. Mitochondrial dysfunction has emerged as an important contributor to HFpEF, yet most studies have examined mitochondrial abnormalities within individual cell types rather than as part of an integrated cardiac microenvironment. This review discusses evidence that cell-type-specific mitochondrial alterations in cardiomyocytes, fibroblasts, and endothelial cells may interact through redox, metabolic, and paracrine signaling to promote diastolic dysfunction, myocardial stiffening, and impaired energetic reserve. In cardiomyocytes, disrupted mitochondrial calcium ( m Ca 2+ ) handling and redox imbalance uncouple ATP production from energetic demand, contributing to Ca 2+ overload, mitochondrial reactive oxygen species (mtROS) generation, and impaired relaxation. In fibroblasts, mitochondrial and metabolic reprogramming support profibrotic activation and extracellular matrix (ECM) deposition. In endothelial cells, mitochondrial dysfunction reduces nitric oxide bioavailability, enhances oxidative stress, and contributes to microvascular dysfunction. Together, these cell-type-specific mitochondrial abnormalities may converge on a redox–calcium–energetics axis that helps explain the dissociation between preserved systolic function and impaired diastolic performance in HFpEF. We further highlight mitochondrial heterogeneity and intercellular crosstalk as potential determinants of disease progression and discuss emerging therapeutic strategies targeting mitochondrial pathways as a rationale for precision approaches in HFpEF.
SN - 2213-2317
ER -