Mitochondrial Permeability Transition: New Findings and Persisting Uncertainties

Several insults cause the inner mitochondrial membrane to abruptly lose osmotic homeostasis, hence initiating a regulated variant of cell death known as ‘mitochondrial permeability transition’ (MPT)-driven necrosis. MPT provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells, including cardiac and cerebral ischemia. Nevertheless, the precise molecular determinants of MPT remain elusive, which considerably hampers the development of clinically implementable cardio- or neuroprotective strategies targeting this process. We summarize recent findings shedding new light on the supramolecular entity that mediates MPT, the so-called ‘permeability transition pore complex’ (PTPC). Moreover, we discuss hitherto unresolved controversies on MPT and analyze the major obstacles that still preclude the complete understanding and therapeutic targeting of this process.