Mitochondrial homeostasis meets novel programmed cell death: crosstalk mechanisms underlying cardiovascular diseases progression

Mitochondrial homeostasis is essential for cardiomyocyte survival and optimal cardiac function. Recent studies have revealed that novel forms of programmed cell death—including ferroptosis, cuproptosis, pyroptosis, necroptosis, NETosis, and disulfidptosis—interact closely with mitochondrial quality control mechanisms, such as mitochondrial dynamics and mitophagy. This review provides a comprehensive overview of the molecular pathways underlying mitochondrial fusion, fission, and selective autophagic clearance, and highlights how disturbances in these processes contribute to cardiovascular disease progression. We further discuss the crosstalk between each form of programmed cell death and mitochondrial quality control, emphasizing the bidirectional influence whereby mitochondrial dysfunction can sensitize cardiomyocytes to cell death, while cell death pathways exacerbate mitochondrial injury. Mechanistic insights are provided for ferroptosis-driven lipid peroxidation, cuproptosis-associated copper dysregulation, pyroptotic inflammasome activation, necroptotic receptor-interacting signaling, NETosis-mediated oxidative stress, and disulfidptosis-induced cytoskeletal collapse. By integrating these findings, we identify critical regulatory nodes and molecular hubs that represent potential therapeutic targets to preserve mitochondrial integrity and prevent cardiomyocyte loss. Finally, we discuss emerging strategies for modulating these pathways and outline future research directions to clarify the interplay between mitochondrial homeostasis and novel programmed cell death in cardiovascular pathology. • Mitophagy and mitochondrial dynamics influence cardiovascular disease progression. • Ferroptosis, cuproptosis, pyroptosis, necroptosis, NETosis, and disulfidptosis crosstalk with mitochondria. • Disrupted mitochondrial quality control exacerbates cardiomyocyte injury. • Targeting these pathways may preserve mitochondrial integrity and cardiac function.