Abstract
Cyclophilin D (CyPD) is an important mitochondrial chaperone protein whose mechanism of action remains a mystery. It is well known for regulating mitochondrial function and coupling of the electron transport chain and ATP synthesis by controlling the mitochondrial permeability transition pore (PTP), but more recent evidence suggests that it may regulate electron transport chain activity. Given its identification as a peptidyl-prolyl, cis-trans isomerase (PPIase), CyPD, is thought to be involved in mitochondrial protein folding, but very few reports demonstrate the presence of this activity. By contrast, CyPD may also perform a scaffolding function, as it binds to a number of important proteins in the mitochondrial matrix and inner mitochondrial membrane. From a clinical perspective, inhibiting CyPD to inhibit PTP opening protects against ischemia–reperfusion injury, making modulation of CyPD activity a potentially important therapeutic goal, but the lack of knowledge about the mechanisms of CyPD’s actions remains problematic for such therapies. Thus, the important yet enigmatic nature of CyPD somehow makes it a master regulator, yet a troublemaker, for mitochondrial function.
Highlights
Cyclophilin D (CyPD, see Table 1 for list of abbreviations) is a member of the cyclophilin family of peptidyl-prolyl, cis-trans isomerases (PPIases) that resides in the mitochondrial matrix
ATP synthase can form synthasomes that contain adenine nucleotide translocator (ANT), PiC, and mitochondrial creatine kinase (mtCK) [12,15], which were found to contain permeability transition pore (PTP)-like activity, as discussed above, and we recently reported that CyPD binds to these synthasomes [52]
Tachycardia preconditioning decreased PTP opening and increased S-glutathionylation of CyPD [137]. These results suggest that these modifications prevent oxidation of C203S residue, a deleterious modification that could help activate the PTP, it should be noted that Bos taurus CyPD lacks this particular residue, yet displays a canonical cyclosporin A (CsA)-sensitive PTP
Summary
Cyclophilin D (CyPD, see Table 1 for list of abbreviations) is a member of the cyclophilin family of peptidyl-prolyl, cis-trans isomerases (PPIases) that resides in the mitochondrial matrix Despite it first being reported in 1990 [1,2], the exact mechanisms by which CyPD regulates and is regulated by mitochondrial function, remain enigmatic. DnaJ heat shock protein family (Hsp40) member C15 mitogen-activated protein kinase 1 electron transport chain glycogen synthase kinase-3β hexokinase heat shock protein 60 heat shock protein 70 heat shock protein 90 inner mitochondrial membrane ischemia–reperfusion injury kilodaltons mammalian sterile 20-like kinase 1 mitochondrial creatine kinase outer mitochondrial membrane oligomycin sensitivity conferral protein oxidative phosphorylation mitochondrial phosphate carrier phenylmethylsulfonyl fluoride peroxisome proliferator-activated receptor-α peptidyl-prolyl, cis-trans isomerase mitochondrial permeability transition pore sirtuin 3 spastic paraplegia 7 signal transducer and activator of transcription 3 tumor necrosis factor type 1 receptor-associated protein. Human gene nomenclature is from GeneCards ([8,9])
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