Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1

Abstract

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial molecular chaperone modulating cellular metabolism and signaling pathways by altering the conformation, activity, and stability of numerous substrate proteins called clients. It exerts its chaperone function as an adaptive response to counter cellular stresses instead of maintaining housekeeping protein homeostasis. However, the stress-adaptive machinery becomes dysregulated to support the progression and maintenance of human diseases, such as cancers; therefore, TRAP1 has been proposed as a promising target protein for anticancer drug development. In this review, by collating recent reports on high-resolution TRAP1 structures and structure–activity relationships of inhibitors, we aimed to provide better insights into the chaperoning mechanism of the emerging drug target and to suggest an efficient strategy for the development of potent TRAP1 inhibitors.

Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy

“…[ 23 ] However, TRAP1‐HIF1α regulation in the retina does not involve SDH and PHD because it was unaffected by treatment with a large excess of succinate (Figure S14A , Supporting Information), the PHD inhibitor dimethyloxalylglycine (DMOG), and a HIF1α mutant (P402A and P564A) lacking PHD hydroxylation sites (Figure S14B , Supporting Information). 17‐Dimethyl‐aminothylamino‐17‐demethoxy‐geldanamycin (DMAG), which inhibits cytoplasmic, but not mitochondrial Hsp90s, [ 24 ] did not affect the stability of HIF1α, indicating that the regulatory mechanism is mitochondria‐specific, [ 25 ] (Figure S14C , Supporting Information).…”

“…Given that TRAP1 is implicated in the generation of mitochondrial reactive oxygen species (ROS), [ 24b ] resulting in the stabilization of HIF1α, [ 31 ] we analyzed retinal ROS production using dihydroethidium (DHE) staining. The levels of DHE staining were comparable between Trap1 +/+ and Trap1 −/− mouse retinas from both STZ and OIR models (Figure S15A,B , Supporting Information), indicating the retinal ROS production is not affected by TRAP1 expression.…”

Chaperones—A New Class of Potential Therapeutic Targets in Alzheimer’s Disease

“…Another interesting chaperone is tumor necrosis factor receptor-associated protein 1 (TRAP1), which functions as an adaptive answer to counter cellular stresses contrary to maintaining housekeeping protein homeostasis [ 64 ]. This protein maintains equity between oxidative phosphorylation (OXPHOS) and aerobic glycolysis [ 65 ].…”

Second international symposium on the chaperone code, 2023

“… 29 Byoung Heon Kang (UNIST, South Korea) presented data demonstrating that TRAP1 contributes to disease pathogenesis by regulating mitochondrial function in non-cancerous cells, such as adipocytes in the tumor microenvironment and retinal cells in ischemic retinopathy, using knockout mice. 30 Additionally, he showed that TRAP1 inhibitors targeting its client binding site, such as mitoquinone and SB-U015, not only exhibit enhanced anticancer activity compared to ATP-mimetic inhibitors 31 , 32 but also show potential applications in treating human diseases caused by mitochondrial dysfunctions. Mark Woodford (State University of New York, Upstate Medical University, USA) presented unpublished work demonstrating phosphorylation of TRAP1 by a mitochondrial population of the proto- oncogene tyrosine kinase c-Abl.…”