Loss of epitranscriptomic control of selenocysteine utilization engages senescence and mitochondrial reprogramming

Redox Biol. 2020 Jan;28:101375. doi: 10.1016/j.redox.2019.101375. Epub 2019 Nov 11.

Abstract

Critically important to the maintenance of the glutathione (GSH) redox cycle are the activities of many selenocysteine-containing GSH metabolizing enzymes whose translation is controlled by the epitranscriptomic writer alkylation repair homolog 8 (ALKBH8). ALKBH8 is a tRNA methyltransferase that methylates the wobble uridine of specific tRNAs to regulate the synthesis of selenoproteins. Here we demonstrate that a deficiency in the writer ALKBH8 (Alkbh8def), alters selenoprotein levels and engages senescence, regulates stress response genes and promotes mitochondrial reprogramming. Alkbh8def mouse embryonic fibroblasts (MEFs) increase many hallmarks of senescence, including senescence associated β-galactosidase, heterocromatic foci, the cyclin dependent kinase inhibitor p16Ink4a, markers of mitochondrial dynamics as well as the senescence associated secretory phenotype (SASP). Alkbh8def cells also acquire a stress resistance phenotype that is accompanied by an increase in a number redox-modifying transcripts. In addition, Alkbh8def MEFs undergo a metabolic shift that is highlighted by a striking increase in the level of uncoupling protein 2 (UCP2) which enhances oxygen consumption and promotes a reliance on glycolytic metabolism. Finally, we have shown that the Alkbh8 deficiency can be exploited and corresponding MEFs are killed by glycolytic inhibition. Our work demonstrates that defects in an epitransciptomic writer promote senescence and mitochondrial reprogramming and unveils a novel adaptive mechanism for coping with defects in selenocysteine utilization.

Keywords: Epitranscriptome; Mitochondria; Selenium; Senescence; Uncoupling protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AlkB Homolog 8, tRNA Methyltransferase / genetics*
  • Animals
  • Cells, Cultured
  • Cellular Senescence
  • Epigenesis, Genetic
  • Gene Deletion
  • Gene Expression Profiling / methods*
  • Humans
  • Mice
  • Mitochondria / metabolism*
  • Oxygen Consumption
  • Selenocysteine / metabolism
  • Uncoupling Protein 2 / metabolism

Substances

  • Uncoupling Protein 2
  • Selenocysteine
  • ALKBH8 protein, human
  • ALKBH8 protein, mouse
  • AlkB Homolog 8, tRNA Methyltransferase