TRPM2 is the second member of the melastatin subfamily of TRP channels to be cloned. Previously called LTRPC2, the human channel consists of 32 exons encoding a protein of 1503 amino acids with a predicted molecular mass of ~170 kDa. The amino acid sequence of human and mouse TRPM2 are 82% identical. TRPM2 channels are widely expressed and are activated by extracellular signals including oxidative stress, TNFα and amyloid β-peptide. Stimulation of cells with these extracellular signals results in production of ADP-ribose (ADPR), which activates the channel by binding to the TRPM2 C-terminal NUDT9-H domain. TRPM2 is also positively regulated by intracellular Ca2+ and calmodulin and is inhibited by acidification. TRPM2 channels function as tetramers and the association of splice variants can modulate its function, especially the short isoform TRPM2-S, which is missing four C-terminal transmembrane domains and the putative Ca2+ pore. TRPM2 plays an essential role in susceptibility to oxidative stress in a number of tissues including heart. Early reports suggested that during hypoxia, ROS are produced that enhance ADPR production, which activates TRPM2 channels, leading to elevations in [Ca2+]i, cytokine production, inflammation, and cell death. However, recent work suggests that this is not necessarily the case. In TRPM2 knock-out (KO) mice injected intraperitoneally with endotoxin, survival was 5 times worse than wild-type (WT), due to enhanced NADPH oxidase-mediated ROS production by KO phagocytes. In the heart, TRPM2 is expressed in the sarcolemma and transverse tubules. Compared to WT mice, baseline cardiac function (+dP/dt, ejection fraction) was not different in either global KO (gKO) or cardiac-specific KO (cKO) mice. After ischemia reperfusion (I/R), both gKO and cKO hearts had significantly lower +dP/dt compared to WT while ROS levels were significantly higher. Superoxide dismutases (SODs) and their upstream regulators (forkhead box transcription factors and hypoxia-inducible factors) were lower. Proteomes of WT-I/R and gKO-I/R hearts showed the largest differences were in mitochondrial dysfunction. Western blots confirmed reduced expression of Complex I subunits and other mitochondrial associated proteins in the KO. KO myocytes and hearts had lower mitochondrial membrane potential (ψm), Ca2+ uptake, ATP production, and O2 consumption rates (OCR), but higher mitochondrial superoxide levels. Reduced mitochondrial Ca2+ uptake was due to both lower ψm and mitochondrial Ca2+ uniporter (MCU) activity. Genetic rescue of gKO myocytes with WT TRPM2 followed by H/R reduced superoxide production. This required Ca2+ influx through TRPM2 since the loss-of-function TRPM2 mutant (E960D) was ineffective. The mitochondrial superoxide scavenger MitoTempo but not the cytosolic scavenger (Tempol) reduced superoxide levels and restored ψm in KO-H/R myocytes. These studies demonstrate that TRPM2 protects heart from I/R and H/R injury by decreasing generation of and enhancing scavenging of ROS in heart. In addition, TRPM2 channels are important in maintaining mitochondrial function and provide the necessary Ca2+ for normal mitochondrial bioenergetics. TRPM2 channels are also highly expressed in a number of malignancies including neuroblastoma. Expression of the dominant negative TRPM2 short isoform (TRPM2-S) inhibited growth of neuroblastoma xenografts through a mechanism involving both reduced mitochondrial calcium uptake and reduced H1F-1/2α expression. Reduced H1F-1/2α expression in cells expressing TRPM2-S was found to contribute to decreased expression of genes involved in glycolysis (lactate dehydrogenase A and enolase 2), oxidant stress (FOXO3a), angiogenesis (VEGF), and mitochondrial function (BNIP3 and NDUFA4L2). The decrease in BNIP3 plays a role in reduced mitophagy, resulting in accumulation of dysfunctional mitochondria and increased ROS, reducing cell viability and tumor growth. Reduced expression of other mitochondrial proteins and reduced Ca2+ entry further compromise mitochondrial function, resulting in lower ATP production and contributing to increased ROS. The finding that TRPM2 is important in mitochondrial function in both protection of cardiac cells from ischemia and in tumor growth and response to chemotherapy suggest it has a basic role in mitochondrial bioenergetics which may apply to a number of physiological systems.