The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

Abstract

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis.

Complex II ambiguities—FADH2 in the electron transfer system

“…( 49 , 57 , 70 , 72 , 133 , 154 , 186 , 244 , 246 , 249 , 251 , 252 , 253 , 254 , 255 , 257 , 262 , 263 , 264 , 267 , 269 , 270 , 272 , 273 , 275 , 276 , 277 , 278 , 279 , 280 , 317 , 319 ). H , the CII ambiguity in FADH 2 →FAD+2H + ( 242 , 243 , 244 , 245 , 246 , 247 , 248 , 249 , 250 , 251 , 252 , 253 , 254 , 255 , 256 , 257 , 258 , 259 , 260 , 261 , 262 , 263 , 264 , 265 , 266 , 267 , 268 , 269 , 270 , 271 , ...…”

Comprehensive overview of how to fade into succinate dehydrogenase dysregulation in cancer cells by naringenin-loaded chitosan nanoparticles

“…Reactive oxygen species (ROS) that are increased in TRAP1 KO cells may be countered by this procedure. After decarboxylation, pyruvate typically enters the TCA cycle and aids in the creation of acetyl-CoA, an essential TCA cycle intermediate [ 23 , 29 ] …”

Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases

“…In addition, a soluble complex of mtHsp70 (mortalin) resides in the matrix (Horst et al, 1997;Havalova et al, 2021), where it performs its protein folding functions with three co-chaperones that have been identified in human: the Hsp70-escort protein 1 (HEP1) and J-domain protein tumorous imaginal disc protein 1 (TID-1), which regulate ATPase activity of mtHsp70, and the NEFs GrpEL1/2 (Sichting et al, 2005;Zhai et al, 2008;Iosefson et al, 2012;Dores-Silva et al, 2013;Havalova et al, 2021). These main matrix chaperone systems are supplemented in mammals by the HSP90 paralog TRAP1, which performs diverse functions including acting as a late-stage folding chaperone for mitochondrial matrix proteins (Joshi et al, 2022).…”