The permeability transition pore (PTP) is a multi-protein complex at contact sites of the inner with the outer mitochondrial membrane. Research over the past years has led to the concept that the PTP occupies a central role in cell death induction. Numerous apoptosis signals convert this protein aggregate into an unspecific pore, thus activating mitochondria for the cellular self-destruction process. Here, we describe the evidence for this and the various approaches being undertaken to elucidate its subunit composition and mode of regulation. In particular, we review data that indicate a role of specific PTP subunits for apoptosis inhibition during tumorigenesis.

Apoptosis-inducing factor (AIF), a mitochondrial NAD(P)H-dependent oxidoreductase, was initially studied as a cell death inducer in a process later named parthanatos. However, it has been revealed that AIF also participates in mitochondrial bioenergetics through interaction with its partner coiled-coil-helix-coiled-coil-helix domain containing 4 (CHCHD4) and involvement in mitochondrial protein import. These dual roles place AIF between pro-survival and pro-death cell fate decisions. In this review, we first describe the structure and the dual functions of AIF, highlighting its structure-function relationships. We then report previously identified AIFM1 mutations and their clinical phenotypes. Finally, we discuss the relevance of AIF in cancer and the potential of targeting this protein for the treatment of cancer.

Diets rich in (poly)phenols are associated with a reduced reduction in the incidence of cardiovascular disorders. While the absorption and metabolism of (poly)phenols has been described, it is not clear how their metabolic fate is affected under pathological conditions. This study evaluated the metabolic fate of berry (poly)phenols in an in vivo model of hypertension as well as the associated microbiota response. Dahl salt-sensitive rats were fed either a low-salt diet (0.26% NaCl) or a high-salt diet (8% NaCl), with or without a berry mixture (blueberries, blackberries, raspberries, Portuguese crowberry and strawberry tree fruit) for 9 weeks. The salt-enriched diet promoted an increase in the urinary excretion of berry (poly)phenol metabolites, while the abundance of these metabolites decreased in faeces, as revealed by UPLC–MS/MS. Moreover, salt and berries modulated gut microbiota composition as demonstrated by 16S rRNA analysis. Some changes in the microbiota composition were associated with the high-salt diet and revealed an expansion of the families Proteobacteria and Erysipelotrichaceae. However, this effect was mitigated by the dietary supplementation with berries. Alterations in the metabolic fate of (poly)phenols occur in parallel with the modulation of gut microbiota in hypertensive rats. Thus, beneficial effects of (poly)phenols could be related with these interlinked modifications, between metabolites and microbiota environments.

Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.