Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure

Mitochondrial dysfunction has long been recognized as a central driver of heart failure (HF) pathogenesis, and emerging evidence highlights that impaired mitochondrial communication, rather than merely energy metabolism dysfunction, plays a pivotal role in the initiation and progression of HF. These communication networks are critical for maintaining cardiac metabolic homeostasis, and their disruption in HF leads to dysregulated energy metabolism, oxidative stress, lipotoxicity, and impaired cardiomyocyte function. This review examines the functional interactions between mitochondria and these organelles in HF, with particular attention to phenotype-specific differences between HF with preserved ejection fraction and HF with reduced ejection fraction. Finally, we summarize current and emerging therapeutic strategies targeting mitochondrial communication, highlighting the potential for phenotype-tailored interventions that restore organelle interplay and metabolic balance in HF.