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Mutations in BRCA2 gene increase the risk for breast cancer and for other cancer types, including pancreatic and prostate cancer. Since its first identification as an oncosupressor in 1995, the best-characterized function of BRCA2 is in the repair of DNA double-strand breaks (DSBs) by homologous recombination. BRCA2 directly interacts with both RAD51 and single-stranded DNA, mediating loading of RAD51 recombinase to sites of single-stranded DNA. In the absence of an efficient homologous recombination pathway, DSBs accumulate resulting in genome instability, thus supporting tumorigenesis. Yet the precise mechanism by which BRCA2 exerts its tumor suppressor function remains unclear. BRCA2 has also been involved in other biological functions including protection of telomere integrity and stalled replication forks, cell cycle progression, transcriptional control and mitophagy. Recently, we and others have reported a role of BRCA2 in modulating cell death programs through a molecular mechanism conserved in yeast and mammals. Here we hypothesize that BRCA2 is a multifunctional protein which exerts specific functions depending on cell stress response pathway. Based on a differential RNA sequencing analysis carried out on yeast cells either growing or undergoing a regulated cell death process, either in the absence or in the presence of BRCA2, we suggest that BRCA2 causes central carbon metabolism reprogramming in response to death stimuli and encourage further investigation on the role of metabolic reprogramming in BRCA2 oncosuppressive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Costanza, Guaragnella, Bobba, Manzari, L’Abbate, Giudice, Picardi, D’Erchia, Pesole and Giannattasio.)

Epithelial-to-mesenchymal transition (EMT) allows epithelial cancer cells to assume mesenchymal features, endowing them with enhanced motility and invasiveness, thus enabling cancer dissemination and metastatic spread. The induction of EMT is orchestrated by EMT-inducing transcription factors that switch on the expression of "mesenchymal" genes and switch off the expression of "epithelial" genes. Mitochondrial dysfunction is a hallmark of cancer and has been associated with progression to a metastatic and drug-resistant phenotype. The mechanistic link between metastasis and mitochondrial dysfunction is gradually emerging. The discovery that mitochondrial dysfunction owing to deregulated mitophagy, depletion of the mitochondrial genome (mitochondrial DNA) or mutations in Krebs' cycle enzymes, such as succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase, activate the EMT gene signature has provided evidence that mitochondrial dysfunction and EMT are interconnected. In this review, we provide an overview of the current knowledge on the role of different types of mitochondrial dysfunction in inducing EMT in cancer cells. We place emphasis on recent advances in the identification of signaling components in the mito-nuclear communication network initiated by dysfunctional mitochondria that promote cellular remodeling and EMT activation in cancer cells.

Mammalian apoptosis and yeast programmed cell death (PCD) share a variety of features including reactive oxygen species production, protease activity and a major role played by mitochondria. In view of this, and of the distinctive characteristics differentiating yeast and multicellular organism PCD, the mitochondrial contribution to cell death in the genetically tractable yeast Saccharomyces cerevisiae has been intensively investigated. In this mini-review we report whether and how yeast mitochondrial function and proteins belonging to oxidative phosphorylation, protein trafficking into and out of mitochondria, and mitochondrial dynamics, play a role in PCD. Since in PCD many processes take place over time, emphasis will be placed on an experimental model based on acetic acid-induced PCD (AA-PCD) which has the unique feature of having been investigated as a function of time. As will be described there are at least two AA-PCD pathways each with a multifaceted role played by mitochondrial components, in particular by cytochrome c.