O-GlcNAcylation is essential for therapeutic mitochondrial transplantation.

Nov 27, 2023

Experts: Ji Hyun Park,Masayoshi Tanaka,Takafumi Nakano,Ester Licastro,Yoshihiko Nakamura,Wenlu Li,Elga Esposito,Emiri T Mandeville,Sherry Hsiang-Yi Chou,MingMing Ning,Eng H Lo,Kazuhide Hayakawa

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.
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).
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.
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.

© 2023. The Author(s).

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ABOUT THE EXPERTS

Ji Hyun Park,Masayoshi Tanaka,Takafumi Nakano,Ester Licastro,Yoshihiko Nakamura,Wenlu Li,Elga Esposito,Emiri T Mandeville,Sherry Hsiang-Yi Chou,MingMing Ning,Eng H Lo,Kazuhide Hayakawa

Ji Hyun Park

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Masayoshi Tanaka

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Takafumi Nakano

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Ester Licastro

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Yoshihiko Nakamura

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Wenlu Li

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Elga Esposito

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Emiri T Mandeville

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Sherry Hsiang-Yi Chou

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Departments of Critical Care Medicine, Neurology and Neurosurgery, University of Pittsburgh, Pittsburgh, PA, USA.

Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA.

MingMing Ning

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.

Clinical Proteomics Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Eng H Lo

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Lo@helix.mgh.harvard.edu.

Kazuhide Hayakawa

Neuroprotection Research Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. khayakawa1@mgh.harvard.edu.