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O-GlcNAcylation is essential for therapeutic mitochondrial transplantation
BACKGROUND: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfa...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676354/ https://www.ncbi.nlm.nih.gov/pubmed/38007588 http://dx.doi.org/10.1038/s43856-023-00402-w |
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author | Park, Ji Hyun Tanaka, Masayoshi Nakano, Takafumi Licastro, Ester Nakamura, Yoshihiko Li, Wenlu Esposito, Elga Mandeville, Emiri T. Chou, Sherry Hsiang-Yi Ning, MingMing Lo, Eng H. Hayakawa, Kazuhide |
author_facet | Park, Ji Hyun Tanaka, Masayoshi Nakano, Takafumi Licastro, Ester Nakamura, Yoshihiko Li, Wenlu Esposito, Elga Mandeville, Emiri T. Chou, Sherry Hsiang-Yi Ning, MingMing Lo, Eng H. Hayakawa, Kazuhide |
author_sort | Park, Ji Hyun |
collection | PubMed |
description | BACKGROUND: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals. METHODS: Mitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc. O-GlcNAcylated mitochondrial proteins were identified by mass spectrometry and the antiglycation ability of O-GlcNAcylated DJ1 was determined by loss-of-function via mutagenesis. Therapeutic efficacy of O-GlcNAcylated mitochondria was assessed in a mouse model of transient focal cerebral ischemia-reperfusion. To explore translational potential, we evaluated O-GlcNAcylated DJ1 in CSF collected from patients with subarachnoid hemorrhagic stroke (SAH). RESULTS: We show that isolated mitochondria are susceptible to advanced glycation end product (AGE) modification, and these glycated mitochondria induce the receptor for advanced glycation end product (RAGE)-mediated autophagy and oxidative stress when transferred into neurons. However, modifying mitochondria with O-GlcNAcylation counteracts glycation, diminishes RAGE-mediated effects, and improves viability of mitochondria recipient neurons. In a mouse model of stroke, treatment with extracellular mitochondria modified by O-GlcNAcylation reduces neuronal injury and improves neurologic deficits. In cerebrospinal fluid (CSF) samples from SAH patients, levels of O-GlcNAcylation in extracellular mitochondria correlate with better clinical outcomes. CONCLUSIONS: These findings suggest that AGE-modification in extracellular mitochondria may induce danger signals, but O-GlcNAcylation can prevent glycation and improve the therapeutic efficacy of transplanted mitochondria in the CNS. |
format | Online Article Text |
id | pubmed-10676354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-106763542023-11-25 O-GlcNAcylation is essential for therapeutic mitochondrial transplantation Park, Ji Hyun Tanaka, Masayoshi Nakano, Takafumi Licastro, Ester Nakamura, Yoshihiko Li, Wenlu Esposito, Elga Mandeville, Emiri T. Chou, Sherry Hsiang-Yi Ning, MingMing Lo, Eng H. Hayakawa, Kazuhide Commun Med (Lond) Article BACKGROUND: Transplantation of mitochondria is increasingly explored as a novel therapy in central nervous system (CNS) injury and disease. However, there are limitations in safety and efficacy because mitochondria are vulnerable in extracellular environments and damaged mitochondria can induce unfavorable danger signals. METHODS: Mitochondrial O-GlcNAc-modification was amplified by recombinant O-GlcNAc transferase (OGT) and UDP-GlcNAc. O-GlcNAcylated mitochondrial proteins were identified by mass spectrometry and the antiglycation ability of O-GlcNAcylated DJ1 was determined by loss-of-function via mutagenesis. Therapeutic efficacy of O-GlcNAcylated mitochondria was assessed in a mouse model of transient focal cerebral ischemia-reperfusion. To explore translational potential, we evaluated O-GlcNAcylated DJ1 in CSF collected from patients with subarachnoid hemorrhagic stroke (SAH). RESULTS: We show that isolated mitochondria are susceptible to advanced glycation end product (AGE) modification, and these glycated mitochondria induce the receptor for advanced glycation end product (RAGE)-mediated autophagy and oxidative stress when transferred into neurons. However, modifying mitochondria with O-GlcNAcylation counteracts glycation, diminishes RAGE-mediated effects, and improves viability of mitochondria recipient neurons. In a mouse model of stroke, treatment with extracellular mitochondria modified by O-GlcNAcylation reduces neuronal injury and improves neurologic deficits. In cerebrospinal fluid (CSF) samples from SAH patients, levels of O-GlcNAcylation in extracellular mitochondria correlate with better clinical outcomes. CONCLUSIONS: These findings suggest that AGE-modification in extracellular mitochondria may induce danger signals, but O-GlcNAcylation can prevent glycation and improve the therapeutic efficacy of transplanted mitochondria in the CNS. Nature Publishing Group UK 2023-11-25 /pmc/articles/PMC10676354/ /pubmed/38007588 http://dx.doi.org/10.1038/s43856-023-00402-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Park, Ji Hyun Tanaka, Masayoshi Nakano, Takafumi Licastro, Ester Nakamura, Yoshihiko Li, Wenlu Esposito, Elga Mandeville, Emiri T. Chou, Sherry Hsiang-Yi Ning, MingMing Lo, Eng H. Hayakawa, Kazuhide O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title | O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title_full | O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title_fullStr | O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title_full_unstemmed | O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title_short | O-GlcNAcylation is essential for therapeutic mitochondrial transplantation |
title_sort | o-glcnacylation is essential for therapeutic mitochondrial transplantation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10676354/ https://www.ncbi.nlm.nih.gov/pubmed/38007588 http://dx.doi.org/10.1038/s43856-023-00402-w |
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