Mitochondrial heterogeneity across cardiac cell types in heart failure with preserved ejection fraction

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 (_mCa²⁺) handling and redox imbalance uncouple ATP production from energetic demand, contributing to Ca²⁺ 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.