SLC25A26 overexpression impairs cell function via mtDNA hypermethylation and rewiring of methyl metabolism

Alessio Menga, Erika M. Palmieri, Antonia Cianciulli, Vittoria Infantino, Massimiliano Mazzone, Antonio Scilimati, Ferdinando Palmieri, Alessandra Castegna, Vito Iacobazzi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)967-984
Number of pages18
JournalFEBS Journal
Volume284
Issue number6
DOIs
Publication statusPublished - Mar 1 2017

Keywords

  • epigenetic mechanisms
  • methyl cycle
  • mtDNA methylation
  • S-adenosylmethionine
  • SLC25A26 mitochondrial carrier

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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