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ORIGINAL RESEARCH article

Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
Volume 16 - 2024 | doi: 10.3389/fnagi.2024.1387931

O-GlcNAc impacts mitophagy via PINK1 dependent pathway

Provisionally accepted
Ibtihal M. Alghusen Ibtihal M. Alghusen 1Marisa S. Carman Marisa S. Carman 1Heather M. Wilkins Heather M. Wilkins 1HALYNA FEDOSYUK HALYNA FEDOSYUK 1Jad Shawa Jad Shawa 1Sophiya J. Ephrame Sophiya J. Ephrame 1Aspin R. Denson Aspin R. Denson 1Russell H. Swerdlow Russell H. Swerdlow 1Chad Slawson Chad Slawson 2*
  • 1 University of Kansas Medical Center, Kansas City, Kansas, United States
  • 2 University of Kansas Medical Center Research Institute, Kansas City, United States

The final, formatted version of the article will be published soon.

    The accumulation of dysfunctional mitochondria is an early feature of Alzheimer Disease (AD). The impaired turnover of damaged mitochondria increases reactive oxygen species production and lowers ATP generation leading to cellular toxicity and neurodegeneration. Interestingly, AD exhibits a disruption in the global posttranslational modification β-N-acetylglucosamine (O-GlcNAc). O-GlcNAc is a ubiquitous single sugar modification found on nuclear, cytoplasmic, and mitochondrial proteins. Cells maintain a homeostatic level of O-GlcNAc by cycling the addition and removal of the sugar by O-GlcNAc transferase (OGT) or O-GlcNAcase (OGA) respectively.We used patient-derived induced pluripotent stem cells, a transgenic mouse model of AD, SH-SY5Y neuroblastoma cell-lines to examine the effect of sustained O-GlcNAcase inhibition by Thiamet-G (TMG) or OGT deficiency on mitophagy using biochemical analyses.Results: Here, we established an essential role for O-GlcNAc in regulating mitophagy (mitochondria-selective autophagy). Stimulating mitophagy using Urolithin A (UA) decreases cellular O-GlcNAc and elevates mitochondrial O-GlcNAc. Sustained elevation in O-GlcNAcylation via pharmacologically inhibiting OGA using Thiamet G (TMG) increases mitochondrial level of mitophagy protein PINK-1 (PTEN-induced kinase-1) and autophagy-related protein light chain 3 (LC3). Moreover, we detected O-GlcNAc on PINK-1 and TMG increases its O-GlcNAcylation level. Conversely, decreasing cellular O-GlcNAcylation by knocking down OGT decreases both PINK1 and LC3 protein expression. Mitochondria isolated from CAMKII-OGT-KO mice also had decreased PINK1 and LC3. Moreover, human brain organoids treated with TMG showed significant elevation in LC3 compared to control. However, TMG treated AD organoids showed no changes in LC3 expression.Collectively, these data demonstrate that O-GlcNAc plays a crucial role in activation and progression of mitophagy, and this activation is disrupted in AD.

    Keywords: O-GlcNAc, mitophagy, PTEN-induced kinase-1, Alzheimer's disease, OGT

    Received: 18 Feb 2024; Accepted: 11 Jul 2024.

    Copyright: © 2024 Alghusen, Carman, Wilkins, FEDOSYUK, Shawa, Ephrame, Denson, Swerdlow and Slawson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Chad Slawson, University of Kansas Medical Center Research Institute, Kansas City, United States

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