Sustained O-GlcNAcylation reprograms mitochondrial function to regulate energy metabolism

Ee Phie Tan, Steven R. McGreal, Stefan Graw, Robert Tessman, Scott J. Koppel, Pramod Dhakal, Zhen Zhang, Miranda Machacek, Natasha E. Zachara, Devin C. Koestler, Kenneth R. Peterson, John P. Thyfault, Russell H. Swerdlow, Partha Krishnamurthy, Luciano DiTacchio, Udayan Apte, Chad Slawson

Research output: Contribution to journalArticlepeer-review

Abstract

Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with β-linked N-acetylglucosamine (O-GlcNAcylation) via overexpression of the O-GlcNAc-regulating enzymes O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in O-GlcNAcylation either by pharmacological or genetic manipulation also alter metabolic function. Sustained O-GlcNAcelevation inSH-SY5Yneuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated O-GlcNAc levels had elongated mitochondria and increased mitochondrial membranepotential, and RNA-sequencing analysis indicated transcriptome reprogramming and down-regulation of the NRF2-mediated antioxidant response. Sustained O-GlcNAcylation in mouse brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated O-GlcNAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in O-GlcNAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.

Original languageEnglish (US)
Pages (from-to)14940-14962
Number of pages23
JournalJournal of Biological Chemistry
Volume292
Issue number36
DOIs
StatePublished - Sep 8 2017

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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