The still uncertain identity of the channel-forming unit(s) of the mitochondrial permeability transition pore

[Display omitted] •The mitochondrial permeability transition compromises cellular homeostasis.•Candidates thought to form the channel unit of the mitochondrial permeability transition pore have not passed loss-of-function genetic tests.•Alternative working models on the channel forming unit(s) of the mitochondrial permeability transition pore still await validation.•Future studies should follow standard guidelines to identify the channel-forming unit(s) of the mitochondrial permeability transition pore. Mitochondria from different organisms can undergo a sudden process of inner membrane unselective leakiness to molecules known as the mitochondrial permeability transition (MPT). This process has been studied for nearly four decades and several proteins have been claimed to constitute, or at least regulate the usually inactive pore responsible for this transition. However, no protein candidate proposed as the actual pore-forming unit has passed rigorous gain- or loss-of-function genetic tests. Here we review evidence for -and against- putative channel-forming components of the MPT pore. We conclude that the structure of the MPT pore still remains largely undefined and suggest that future studies should follow established technical considerations to unambiguously consolidate the channel forming constituent(s) of the MPT pore.