Mitochondrial homeostasis in heart failure with preserved ejection fraction: from metabolic remodeling to multi-organ crosstalk

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents a predominant heart failure phenotype characterized by intricate pathophysiology and an escalating global prevalence. Beyond classical hemodynamic disturbances, emerging evidence identifies mitochondrial dysfunction as a central mechanism in HFpEF pathogenesis. This review synthesizes the pivotal mitochondrial aberrations driving HFpEF, including impaired bioenergetics, disrupted mitochondrial quality control, oxidative stress, and Ca2+ dyshomeostasis, particularly under the burden of cardiometabolic stressors. Importantly, we highlight that HFpEF represents a multisystem disorder wherein the mitochondria of adipose tissue, the vasculature, the immune system, and skeletal muscle actively contribute to the pathological process. By reclassifying HFpEF as a bioenergetic failure, we hope to provide a conceptual framework for the development of integrated, mitochondria-targeted therapeutic strategies.