We and others previously reported that endogenous p53 can be located at mitochondria in the absence of stress, suggesting that p53 has a role in the normal physiology of this organelle. the aim of this study was to characterize in unstressed cells the intramitochondrial localization of p53 and identify new partners and functions of p53 in mitochondria. We find that the intramitochondrial pool of p53 is located in the intermembrane space and the matrix. of note, unstressed HCt116 p53+/+ cells simultaneously show increased o 2 consumption and decreased mitochondrial superoxide production compared with their p53-null counterpart. this data was confirmed by stable H1299 cell lines expressing low levels of p53 specifically targeted to the matrix. Using immunoprecipitation and mass spectrometry, we identified the oligomycin sensitivity-conferring protein (oSCP), a subunit of the F1F0-atP synthase complex, as a new partner of endogenous p53, specifically interacting with p53 localized in the matrix. Interestingly, this interaction seems implicated in mitochondrial p53 localization. Moreover, p53 localized in the matrix promotes the assembly of F1F0-atP synthase. taking into account that deregulations of mitochondrial respiration and reactive oxygen species production are tightly linked to cancer development, we suggest that mitochondrial p53 may be an important regulator of normal mitochondrial and cellular physiology, potentially exerting tumor suppression activity inside mitochondria.

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In this study, we have compared several features of cell death triggered by classical inducers of apoptotic pathways (etoposide and tumour necrosis factor (TNF)-α) versus exogenous reactive oxygen species (ROS; hydrogen peroxide (H₂O₂), tert-butyl hydroperoxide (t-BHP)) or a ROS generator (paraquat). Our aim was to characterize relationships that exist between ROS, mitochondrial perturbations, Bcl-2 and caspases, depending on source and identity of ROS. First, we have found that these five inducers trigger oxidative stress, mitochondrial membrane permeabilization (MMP), cytochrome c (cyt c) release from mitochondria and cell death. In each case, cell death could be inhibited by several antioxidants, showing that it is primarily ROS dependent. Second, we have highlighted that during etoposide or TNF-α treatments, intracellular ROS level, MMP and cell death are all regulated by caspases and Bcl-2, with caspases acting early in the process. Third, we have demonstrated that H₂O₂-induced cell death shares many of these characteristics with etoposide and TNF-α, whereas t-BHP induces both caspase-dependent and caspase-independent cell death. Surprisingly, paraquat-induced cell death, which harbours some characteristics of apoptosis such as cyt c release and caspase-3 activation, is not modulated by Bcl-2 and caspase inhibitors, suggesting that paraquat also triggers non-apoptotic cell death signals. On the one hand, these results show that endogenous or exogenous ROS can trigger multiple cell death pathways with Bcl-2 and caspases acting differentially. On the other hand, they suggest that H₂O₂ could be an important mediator of etoposide and TNF-α-dependent cell death since these inducers trigger similar phenotypes.

Sideroflexins (SLC56 family) are highly conserved multi-spanning transmembrane proteins inserted in the inner mitochondrial membrane in eukaryotes. Few data are available on their molecular function, but since their first description, they were thought to be metabolite transporters probably required for iron utilization inside the mitochondrion. Such as numerous mitochondrial transporters, sideroflexins remain poorly characterized. The prototypic member SFXN1 has been recently identified as the previously unknown mitochondrial transporter of serine. Nevertheless, pending questions on the molecular function of sideroflexins remain unsolved, especially their link with iron metabolism. Here, we review the current knowledge on sideroflexins, their presumed mitochondrial functions and the sparse—but growing—evidence linking sideroflexins to iron homeostasis and iron-sulfur cluster biogenesis. Since an imbalance in iron homeostasis can be detrimental at the cellular and organismal levels, we also investigate the relationship between sideroflexins, iron and physiological disorders. Investigating Sideroflexins’ functions constitutes an emerging research field of great interest and will certainly lead to the main discoveries of mitochondrial physio-pathology.