TRAP1 plays an important role in protecting cells against oxidative stress and apoptosis. To this purpose it has been observed that TRAP1 suppression in mitochondria induces the apoptosis process by means of ROS production. What is more TRAP1 overexpression decreases ROS production and preserves mitochondrial membrane potential during the ischemia-like condition of glucose deprivation and preserves ATP levels and cell viability during oxygen-glucose deprivation. TRAP1 protects cells from granzyme M-mediated apoptosis by preventing the accumulation of ROS. The cleavage of TRAP1 by the granzyme abolishes its antagonistic function to ROS, and leads to ROS accumulation. It has been proposed that mitochondrial homeostasis is differentially regulated in tumor versus normal cells, in part due to elevated expression of TRAP1 in mitochondria. The overexpression of TRAP1 might buffer mitochondrial proteins from direct damage caused by exposure to prolonged oxidative stress. To this regard, it was reported that TRAP1 is a member of a prosurvival mitochondrial pathway highly activated in tumor cells that antagonizes the proapototic activity of cyclophilin D (CypD), a protein involved in the regulation of the mitochondrial permeability transition pore.
TRAP1-overexpression induces a decrease in levels of ROS, Caveolin-1, glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD) as well as of the senescence-associated beta-galactosidase in cells treated with deferoxamine (DFO), an iron chelator responsible of mitochondrial dysfunction and senescence-like cellular morphology. It has been shown that TRAP1 is a MYC target, thus it may be considered involved in increased apoptosis in MYC-overexpressing cells and accountable for the elevated susceptibility of such cells to tumor necrosis factor alpha-mediated apoptosis.

Hypoxia conditions induce an up-regulation of protein levels of TRAP1 in osteoarthritic chondrocyte and in cartilage tissue, and in cardiomyocytes, in which TRAP1 plays a protective role by regulating the opening of the mitochondrial permeability transition pore.

TRAP1 is phosphorylated by PINK1, a serine/threonine protein kinase that localizes to mitochondria, and this phosphorylation mediates the PINK1 protective effects against oxidative stress-induced cell death by preventing the release of cytochrome c from mitochondria. PINK1 mutations that cause the Parkinson disease induce a reduced phosporylation of TRAP1 and thus a sensitization of the cells to the lethal effects of reactive oxygen species.

The expression of TRAP1 in heat stress conditions is modulated by the common variability of the mitochondrial DNA. In fact TRAP1 is over-expressed at both mRNA and intra-mitochondrial protein levels in cybrid line harbouring mtDNA of haplogroup H than in the other cybrid lines (lines J, U, X, T).