A TRPM2-Driven Signalling Cycle Orchestrates Abnormal Inter-Organelle Crosstalk in Cardiovascular and Metabolic Diseases

Cardiovascular and metabolic disorders significantly reduce healthspan and lifespan, with oxidative stress being a major contributing factor. Oxidative stress, marked by elevated reactive oxygen species (ROS), disrupts cellular and systemic functions. One proposed mechanism involves TRPM2 (Transient Receptor Potential Melastatin2)-dependent Ca2+ dysregulation. These channels, activated by ROS (via ADP-ribose), not only respond to ROS but also amplify it, creating a self-sustaining cycle. Recent studies suggest that TRPM2 activation triggers a cascade of signals from intracellular organelles, enhancing ROS production and affecting cell physiology and viability. This review examines the role of TRPM2 channels in oxidative stress-associated cardiovascular and metabolic diseases. Oxidative stress induces TRPM2-mediated Ca2+ influx, leading to lysosomal damage and the release of Zn2+ from lysosomal stores to the mitochondria. In mitochondria, Zn2+ facilitates electron leakage from respiratory complexes, reducing membrane potential, increasing ROS production, and accelerating mitochondrial degradation. Excess ROS activates PARP1 in the nucleus, releasing ADP-ribose, a TRPM2 agonist, thus perpetuating the cycle. Lysosomes act as Ca2+-sensitive signalling platforms, delivering toxic Zn2+ signals to mitochondria. This represents a paradigm shift, proposing that the toxic effects of Ca2+ on mitochondria are not direct, but are instead mediated by lysosomes and subsequent Zn2+ release. This cycle exhibits a ‘domino’ effect, causing sequential and progressive decline in the function of lysosomes, mitochondria, and the nucleus—hallmarks of ageing and oxidative stress-related cardiovascular and metabolic diseases. These insights could lead to new therapeutic strategies for addressing the widespread issue of cardiovascular and metabolic diseases.