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SLC 25A26 overexpression impairs cell function via mt DNA hypermethylation and rewiring of methyl metabolism
Author(s) -
Menga Alessio,
Palmieri Erika M.,
Cianciulli Antonia,
Infantino Vittoria,
Mazzone Massimiliano,
Scilimati Antonio,
Palmieri Ferdinando,
Castegna Alessandra,
Iacobazzi Vito
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14028
Subject(s) - mitochondrion , cell cycle , biology , dna methylation , microbiology and biotechnology , apoptosis , mitochondrial dna , cancer cell , chemistry , gene , gene expression , cancer , biochemistry , genetics
Cancer cells down‐regulate different genes to give them a selective advantage in invasiveness and/or metastasis. The SLC 25A26 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 SLC 25A26 is down‐regulated due to gene promoter hypermethylation, as a mechanism to promote cell survival and proliferation. Furthermore, overexpression of SLC 25A26 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.