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

Authors

Thomas J. Begley, University at Albany, State University of New York
Andrea Leonardi, University at Albany, State University of New York
May Y. Lee, SUNY Polytechnic Institute
J. Andres Melendez, SUNY Polytechnic Institute

Preview

Document Type

Article

Publication Date

1-2020

DOI

https://doi.org/10.1016/j.redox.2019.101375

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 (Alkbh8^def), alters selenoprotein levels and engages senescence, regulates stress response genes and promotes mitochondrial reprogramming. Alkbh8^def mouse embryonic fibroblasts (MEFs) increase many hallmarks of senescence, including senescence associated β-galactosidase, heterocromatic foci, the cyclin dependent kinase inhibitor p16^Ink4a, markers of mitochondrial dynamics as well as the senescence associated secretory phenotype (SASP). Alkbh8^def cells also acquire a stress resistance phenotype that is accompanied by an increase in a number redox-modifying transcripts. In addition, Alkbh8^def 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.

Comments

This is the Publisher’s PDF of the following article made available by Redox Biology: https://doi.org/10.1016/j.redox.2019.101375

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Begley, Thomas J.; Leonardi, Andrea; Lee, May Y.; and Melendez, J. Andres, "Loss of epitranscriptomic control of selenocysteine utilization engages senescence and mitochondrial reprogramming" (2020). Biological Sciences Faculty Scholarship. 28.
https://scholarsarchive.library.albany.edu/biology_fac_scholar/28