SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism. (21st February 2017)

• Record Type: Journal Article
• Authors: Menga, Alessio; Palmieri, Erika M.; Cianciulli, Antonia; Infantino, Vittoria; Mazzone, Massimiliano; Scilimati, Antonio; Palmieri, Ferdinando; Castegna, Alessandra; Iacobazzi, Vito
• Is Part Of: FEBS journal. Volume 284:Number 6(2017)
• Page Start: 967
• Page End: 984
• Publication Date: 2017-02-21
• Subjects: epigenetic mechanisms -- methyl cycle -- mtDNA methylation -- S‐adenosylmethionine -- SLC25A26 mitochondrial carrier; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14028
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : Cancer cells down‐regulate different genes to give them a selective advantage in invasiveness and/or metastasis. The SLC25A26 gene encodes the mitochondrial carrier that catalyzes the import of S ‐adenosylmethionine (SAM) into the mitochondrial matrix, required for mitochondrial methylation processes, and is down‐regulated in cervical cancer cells. In this study we show that SLC25A26 is down‐regulated due to gene promoter hypermethylation, as a mechanism to promote cell survival and proliferation. Furthermore, overexpression of SLC25A26 in CaSki cells increases mitochondrial SAM availability and promotes hypermethylation of mitochondrial DNA, leading to decreased expression of key respiratory complex subunits, reduction of mitochondrial ATP and release of cytochrome c . In addition, increased SAM transport into mitochondria leads to impairment of the methionine cycle with accumulation of homocysteine at the expense of glutathione, which is strongly reduced. All these events concur to arrest the cell cycle in the S phase, induce apoptosis and enhance chemosensitivity of SAM carrier‐overexpressing CaSki cells to cisplatin. Abstract : Overexpression of the SLC25A26 gene, which encodes the mitochondrial S ‐adenosylmethionine carrier, in CaSki cells increases mitochondrial S ‐adenosylmethionine availability and promotes hypermethylation of mtDNA. This leads to a bioenergetic functional failure of the mitochondria, apoptosis and enhanced chemosensitivity to cisplatin.