The impact of the mitochondrial permeability transition (MPT) on cellular physiology is well characterized. In contrast, the composition and mode of action of the permeability transition pore complex (PTPC), the supramolecular entity that initiates MPT, remain to be elucidated. Specifically, the precise contribution of the mitochondrial FF ATP synthase (or subunits thereof) to MPT is a matter of debate. We demonstrate that FF ATP synthase dimers dissociate as the PTPC opens upon MPT induction. Stabilizing FF ATP synthase dimers by genetic approaches inhibits PTPC opening and MPT Specific mutations in the FF ATP synthase c subunit that alter C-ring conformation sensitize cells to MPT induction, which can be reverted by stabilizing FF ATP synthase dimers. Destabilizing FF ATP synthase dimers fails to trigger PTPC opening in the presence of mutants of the c subunit that inhibit MPT The current study does not provide direct evidence that the C-ring is the long-sought pore-forming subunit of the PTPC, but reveals that PTPC opening requires the dissociation of FF ATP synthase dimers and involves the C-ring.

Mitochondria and endoplasmic reticulum (ER) are fundamental in the control of cell physiology regulating several signal transduction pathways. They continuously communicate exchanging messages in their contact sites called MAMs (Mitochondria-Associated Membranes). MAMs are specific microdomains acting as a platform for the sorting of vital and dangerous signals.In recent years increasing evidence reported that multiple scaffold proteins and regulatory factors localize to this subcellular fraction suggesting MAMs as hotspot signaling domains. In this review we describe the current knowledge about MAMs' dynamics and processes, which provided new correlations between MAMs' dysfunctions and human diseases. Infact, MAMs machinery is strictly connected with several pathologies, like neurodegeneration, diabetes and mainly cancer. These pathological events are characterized by alterations in the normal communication between ER and mitochondria, leading to deep metabolic defects that contribute to the progression of the diseases.MFN2 defining it as a ER-mitochondria tether whose ablation decreases interorganellar juxtaposition and communication (Naon et al., 2016). This topic is still controversial with opposite results (Filadi et al., 2017) which allow for further considerations about MFN2 functions. Another protein complex whose function is to modulate ER-mitochondria juxtaposition is the complex formed by inositol 1,4,5-trisphosphate receptors (IP3Rs), the voltage-dependent anion channel (VDAC) and the OMM chaperone Grp75 as described in Figure 1 (Szabadkai et al., 2006). This interaction is considered functional because it promotes the efficient transfer of calcium from the ER to mitochondria. In fact, silencing of Grp75 in HeLa cells abolished Ca 2+ accumulation in mitochondria, highlighting chaperone-mediated conformational coupling between the IP3R and mitochondrial machinery. Nevertheless, a recent study of Bartok et al. reveals a non-canonical and structural role for the IP3Rs independently from calcium flux (Bartok et al., 2019).They display that IP3Rs are required for maintaining ER-mitochondrial contacts. Recently, a study of the Transglutaminase type 2 (TG2) interactome showed an enzymatic interaction with GRP75 in the MAM fraction (D'Eletto et al., 2018). In fact, silencing of the TG2-GRP75 complex leads to an increase in the interaction between IP3R-3 and GRP75, a reduction in the number of ER-mitochondria contact sites, impairment of ER-mitochondrial Ca 2+ flux and an altered MAM proteome profile. Furthermore, the complex formed between ER vesicle-associated membrane protein-associated protein B (VAPB) and PTPIP51 regulates the modulation of Ca 2+ homeostasis by MAMs (De Vos et al., 2012).

According to the ‘multiple‐hit’ hypothesis, several factors can act simultaneously in nonalcoholic fatty liver disease (NAFLD) progression. Increased nitro‐oxidative (nitroso‐oxidative) stress may be considered one of the main contributors involved in the development and risk of NAFLD progression to nonalcoholic steatohepatitis (NASH) characterized by inflammation and fibrosis. Moreover, it has been repeatedly postulated that mitochondrial abnormalities are closely related to the development and progression of liver steatosis and NAFLD pathogenesis. However, it is difficult to determine with certainty whether mitochondrial dysfunction or oxidative stress are primary events or a simple consequence of NAFLD development. On the one hand, increasing lipid accumulation in hepatocytes could cause a wide range of effects from mild to severe mitochondrial damage with a negative impact on cell fate. This can start the cascade of events, including an increase of cellular reactive nitrogen species (RNS) and reactive oxygen species (ROS) production that promotes disease progression from simple steatosis to more severe NAFLD stages. On the other hand, progressing mitochondrial bioenergetic catastrophe and oxidative stress manifestation could be considered accompanying events in the vast spectrum of abnormalities observed during the transition from NAFL to NASH and cirrhosis. This review updates our current understanding of NAFLD pathogenesis and clarifies whether mitochondrial dysfunction and ROS/RNS are culprits or bystanders of NAFLD progression.

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