Mitochondrial permeability transition in cardiac ischemia–reperfusion: whether cyclophilin D is a viable target for cardioprotection?

Abstract

Growing number of studies provide strong evidence that the mitochondrial permeability transition pore (PTP), a non-selective channel in the inner mitochondrial membrane, is involved in the pathogenesis of cardiac ischemia–reperfusion and can be targeted to attenuate reperfusion-induced damage to the myocardium. The molecular identity of the PTP remains unknown and cyclophilin D is the only protein commonly accepted as a major regulator of the PTP opening. Therefore, cyclophilin D is an attractive target for pharmacological or genetic therapies to reduce ischemia–reperfusion injury in various animal models and humans. Most animal studies demonstrated cardioprotective effects of PTP inhibition; however, a recent large clinical trial conducted by international groups demonstrated that cyclosporine A, a cyclophilin D inhibitor, failed to protect the heart in patients with myocardial infarction. These studies, among others, raise the question of whether cyclophilin D, which plays an important physiological role in the regulation of cell metabolism and mitochondrial bioenergetics, is a viable target for cardioprotection. This review discusses previous studies to provide comprehensive information on the physiological role of cyclophilin D as well as PTP opening in the cell that can be taken into consideration for the development of new PTP inhibitors.

Apaf-1 Pyroptosome Senses Mitochondrial Permeability Transition

“…Persistent MPT is mediated by the irreversible opening of a multiprotein complex pore, called MPTP (Izzo et al, 2016). Although the exact molecular components of MPTP remain unclear and may vary in a context dependent manner, several proteins including adenine nucleotide translocator (ANT), cyclophilin D (CYPD) and voltage-dependent anion channel (VDAC) have been considered as functional components(Baines et al, 2005; Javadov et al, 2017; Karch and Molkentin, 2014; Nakagawa et al, 2005; Zhivotovsky et al, 2009). We screened a panel of inhibitors to these MPTP components.…”

Inhibition of the mitochondrial permeability transition exerts sex-specific stimulatory effect on fracture repair

“…As more effective and specific CypD inhibitors are being developed, e.g. NIM811 and JW47 (16,17), our findings suggest CypD/MPTP inhibition as a new avenue for bone anabolic strategies in fracture repair.…”

“…This work, along with previous work in our lab, provides support for the role of mitochondria, as key regulators of the osteogenic program and bone formation and repair. We posit that CypD inhibition using pharmacological inhibitors of CypD, such as NIM811, Debio025, and JW47 (16,17), as potential candidates to induce bone formation and promote bone repair especially in aging and other pathologies.…”

“…The earliest known inhibitor of CypD and, thus of MPTP opening is the immunosuppressor, cyclosporine A (CsA). Its immunosuppressive function stems from its ability to bind and inhibit calcineurin (16). Non-immunosuppressive derivatives of CsA have been developed, such as NIM811, Debio025, and most recently JW47 (16)(17)(18).…”

“…Its immunosuppressive function stems from its ability to bind and inhibit calcineurin (16). Non-immunosuppressive derivatives of CsA have been developed, such as NIM811, Debio025, and most recently JW47 (16)(17)(18). CypD genetic deletion or pharmacological inhibition are extensively used in studies of the heart and brain pathologies, where it has been shown to protect against injury, e.g.…”