Post-translational modifications of mitochondrion-related proteins: integrative orchestrators of cell fate networks in cardiovascular disease

Cardiovascular disease remains the leading cause of global mortality, with mitochondrial dysfunction playing a central pathogenic role. Post-translational modifications act as fundamental regulators of mitochondrial quality control. Yet, how mitochondrial post-translational modifications integrate stress signals to direct cell fate among diverse regulated cell death pathways in cardiovascular disease remains incompletely understood. This review proposes a conceptual framework in which mitochondrial post-translational modifications act as the master conductors of an integrated network linking mitochondrial homeostasis to cellular demise. We first outline the pivotal roles of mitochondrial quality control in cardiovascular disease and detail their precise mechanisms governed by mitochondrial post-translational modifications over each process. We then delineate how mitochondrial post-translational modifications critically regulate the initiation and execution of apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, evaluating their distinct contributions to cardiovascular pathophysiology. Furthermore, we highlight the extensive crosstalk and convergence among these death modalities at the mitochondrial level, emphasizing the role of mitochondrial post-translational modification signatures in amplifying death signals or triggering modality switching. By synthesizing recent discoveries, this work connects dynamic protein-level modifications to cell fate outcomes, offering a theoretical basis for future therapeutic strategies aimed at rebalancing the network of mitochondrial post-translational modifications to combat heart failure and other cardiovascular diseases.