The mitochondrial permeability transition (MPT) consists of an abrupt increase in the permeability of the inner mitochondrial membrane to low molecular weight solutes, resulting in the osmotic breakout of the organelle. MPT drives cell death and provides an etiological contribution to several human disorders characterized by the acute loss of post-mitotic cells. These conditions include ischemia/reperfusion injury, cancer and neurodegenerative disorders. However, precise knowledge of the structure and regulators of the supramolecular entity that induces MPT, the so-called permeability transition pore complex (PTPC), is lacking and this constitutes a substantial obstacle in the development of MPT-targeting agents with clinical applications. Despite the intense experimental interest generated by MPT throughout the last two decades, the precise molecular composition of the PTPC remains elusive.
Recently, thanks to monitoring MPT in living cells using fluorescence-imaging-based techniques (Bonora et al., 2016), two proteins were added to the list of PTPC components: the mitochondrial F1FO ATP synthase, particularly the c subunit of the FO domain (which in humans is encoded by three genes, ATP5G1, ATP5G2 and ATP5G3), and the SPG7 paraplegin matrix AAA peptidase subunit
We were the first to show that the mitochondrial megachannel is formed/created by a ring composed of the mitochondrial ATP synthase c-subunits (Bonora et al., 2013; Cell Cycle). In that same year after the publication of our work some new information started to come out, which confirmed our discovery. The issue turned out to be interesting enough that we are still studying it with use of the newest techniques of molecular biology and genetic engineering. The results of our recent findings I this research area have been published by us in (Bonora et al., 2015; Oncogene), (Morciano et al., 2015; J Mol Cell Cardiol), (Bonora et al., 2017; EMBO Rep.), (Bonora et al., 2016; Nature Protocols) and (Morciano et al., 2018; J Med Chem.).
