Structural mechanisms of cyclophilin D-dependent control of the mitochondrial permeability transition pore

Abstract

Background Opening of the Mitochondrial Permeability Transition pore is the underlying cause of cellular dysfunction during diverse pathological situations. Although this bioenergetic entity has been studied extensively, its molecular componentry is constantly debated. Cyclophilin D is the only universally accepted modulator of this channel and its selective ligands have been proposed as therapeutic agents with the potential to regulate pore opening during disease. Scope of review This review aims to recapitulate known molecular determinants necessary for Cyclophilin D activity regulation and binding to proposed pore constituents therefore regulating the mitochondrial permeability transition pore. Major conclusions While the main target of Cyclophilin D is still a matter of further research, permeability transition is finely regulated by post-translational modifications of this isomerase and its catalytic activity facilitates pore opening. General significance Complete elucidation of the molecular determinants required for Cyclophilin D-mediated control of the mitochondrial permeability transition pore will allow the rational design of therapies aiming to control disease phenotypes associated with the occurrence of this unselective channel.

Mitochondrial dysfunction induced by leflunomide and its active metabolite

“…The binding of bongkrekic acid locks ANT in a conformation to facilitate MPTP blockage (Fiore et al, 1998). It has also been proposed that cyclosporine A may modulate the pore-forming activity of F 1 F O ATP synthase through ANT or PiC that binds with CypD, which may explain the mild MPTP blockage effects of cyclosporine A observed in this study (Gutierrez-Aguilar and Baines, 2015; Karch and Molkentin, 2014). On the other hand, in HepG2 cells, it is possible that CypD is more sensitive than ANT in response to mitotoxicants.…”

“…In contrast, the protective effects of the CypD inhibitor cyclosporine A were less pronounced. In general, ANT is considered as a structural component of MPTP, but evidence also suggests that ANT can act a regulator of MPTP activity in association with CypD, mitochondrial phosphate carrier (PiC), F 1 F O ATP synthase or other pore-forming components (Baines, 2009; Gutierrez-Aguilar and Baines, 2015; Karch and Molkentin, 2014). The binding of bongkrekic acid locks ANT in a conformation to facilitate MPTP blockage (Fiore et al, 1998).…”

Esculetin induces apoptosis in human gastric cancer cells through a cyclophilin D-mediated mitochondrial permeability transition pore associated with ROS

“…5B and C). We found that the esculetin-induced collapse of the MMP was prevented by treatment with CsA (CsA can specifically interact with CypD (a component of MPTP) and affects pore permeability) [29,30], but not by treatment with BA (an inhibitor of adenine nucleotide translocase (ANT), which is also a component of MPTP) [31] or the antioxidant, NAC ( Fig. 5B and C).…”

Mitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease

“…Over-activation of mPTP has been proposed to be a critical mechanism underlying compromised mitochondrial calcium buffering capacity in AD [208, 209, 213–217]. Excess mPTP leads to decreased mitochondrial calcium retention, collapsed mitochondrial membrane potential, reduced OXPHOS efficiency, and elevated ROS production and release, as well as ruptured mitochondrial membrane, eventually cell death [218, 219]. Although the exact molecular identity of mPTP still remains to be elucidated, a mitochondrial matrix protein called cyclophilin D(CypD) is a determined key regulator of mPTP formation [218, 219].…”