Rev1 deficiency induces a metabolic shift in MEFs that can be manipulated by the NAD+ precursor nicotinamide riboside

Sharath Anugula; Zhiquan Li; Yuan Li; Alexander Hendriksen; Peter Bjarn Christensen; Lin Wang; Jonathan M Monk; Niels de Wind; Vilhelm A Bohr; Claus Desler; Robert K Naviaux; Lene Juel Rasmussen

doi:10.1016/j.heliyon.2023.e17392

Rev1 deficiency induces a metabolic shift in MEFs that can be manipulated by the NAD⁺ precursor nicotinamide riboside

Heliyon. 2023 Jun 19;9(6):e17392. doi: 10.1016/j.heliyon.2023.e17392. eCollection 2023 Jun.

Authors

Affiliations

¹ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200, Copenhagen, Denmark.
² Departments of Medicine, Pediatrics, and Pathology, University of California, San Diego School of Medicine, 214 Dickinson Street, Building CTF, Room C107, San Diego, CA, 92103, USA.
³ Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
⁴ Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.

Abstract

Replication stress, caused by Rev1 deficiency, is associated with mitochondrial dysfunction, and metabolic stress. However, the overall metabolic alterations and possible interventions to rescue the deficits due to Rev1 loss remain unclear. Here, we report that loss of Rev1 leads to intense changes in metabolites and that this can be manipulated by NAD ⁺ supplementation. Autophagy decreases in Rev1^-/- mouse embryonic fibroblasts (MEFs) and can be restored by supplementing the NAD⁺ precursor nicotinamide riboside (NR). The abnormal mitochondrial morphology in Rev1^-/- MEFs can be partially reversed by NR supplementation, which also protects the mitochondrial cristae from rotenone-induced degeneration. In nematodes rev-1 deficiency causes sensitivity to oxidative stress but this cannot be rescued by NR supplementation. In conclusion, Rev1 deficiency leads to metabolic dysregulation of especially lipid and nucleotide metabolism, impaired autophagy, and mitochondrial anomalies, and all of these phenotypes can be improved by NR replenishment in MEFs.

Keywords: Autophagy; Healthspan; Mitochondria; NAD+; Nicotinamide riboside; Replication stress; Rev1.