Targeting the mitochondrial permeability transition pore for drug discovery: Challenges and opportunities

Several drug targets have been amenable to drug discovery pursuit not until the characterization of the mitochondrial permeability transition pore (MPTP), a pore with an undefined molecular identity that forms on the inner mitochondrial membrane upon mitochondrial permeability transition (MPT) under the influence of calcium overload and oxidative stress. The opening of the pore which is presumed to cause cell death in certain human diseases also has implications under physiological parlance. Different models for this pore have been postulated following its first identification in the last six decades. The mitochondrial community has witnessed many protein candidates such as; voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), Mitochondrial phosphate carrier (PiC), Spastic Paralegin (SPG7), disordered proteins, and F1Fo ATPase. However, genetic studies have cast out most of these candidates with only F1Fo ATPase currently under intense argument. Cyclophilin D (CyPD) remains the widely accepted positive regulator of the MPTP known to date, but no drug candidate has emerged as its inhibitor, raising concern issues for therapeutics. Thus, in this review, we discuss various models of MPTP reported with the hope of stimulating further research in this field. We went beyond the classical description of the MPTP to ascribe a 'two-edged sword property' to the pore for therapeutic function in human disease because its inhibition and activation have pharmacological relevance. We suggested putative proteins upstream to CyPD that can regulate its activity and prevent cell deaths in neurodegenerative disease and ischemia-reperfusion injury.

Automated summary

The mitochondrial permeability transition pore (MPTP) is a pore formed on the inner mitochondrial membrane under calcium overload and oxidative stress, which can cause cell death and has physiological significance. Various models of MPTP have been proposed, with F1Fo ATPase being the most debated candidate protein. Cyclophilin D (CyPD) is widely accepted as the positive regulator of MPTP, but no drug candidate as its inhibitor has emerged.