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
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.
Commun Med (Lond). 2023 Nov 25;3(1):169. doi: 10.1038/s43856-023-00402-w.
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.
线粒体移植作为一种治疗中枢神经系统（CNS）损伤和疾病的新疗法，正受到越来越多的探索。然而，由于线粒体在细胞外环境中易受损，且受损线粒体可诱导不良危险信号，其在安全性和有效性方面存在局限性。
通过重组O-连接N-乙酰葡糖胺转移酶（OGT）和尿苷二磷酸-N-乙酰葡糖胺（UDP-GlcNAc）增强线粒体的O-连接N-乙酰葡糖胺修饰。通过质谱鉴定O-连接N-乙酰葡糖胺化的线粒体蛋白，并通过诱变功能丧失确定O-连接N-乙酰葡糖胺化的DJ1的抗糖化能力。在短暂性局灶性脑缺血再灌注小鼠模型中评估O-连接N-乙酰葡糖胺化线粒体的治疗效果。为了探索其转化潜力，我们在蛛网膜下腔出血性中风（SAH）患者的脑脊液中评估了O-连接N-乙酰葡糖胺化的DJ1。
我们发现分离的线粒体易受晚期糖基化终产物（AGE）修饰，这些糖化线粒体在转移到神经元中时会诱导晚期糖基化终产物受体（RAGE）介导的自噬和氧化应激。然而，用O-连接N-乙酰葡糖胺修饰线粒体可抵消糖化作用，减少RAGE介导的影响，并提高线粒体受体神经元的活力。在中风小鼠模型中，用O-连接N-乙酰葡糖胺修饰的细胞外线粒体进行治疗可减少神经元损伤并改善神经功能缺损。在SAH患者的脑脊液样本中，细胞外线粒体中的O-连接N-乙酰葡糖胺化水平与更好的临床结果相关。
这些发现表明，细胞外线粒体中的AGE修饰可能会诱导危险信号，但O-连接N-乙酰葡糖胺化可以防止糖化，并提高移植线粒体在中枢神经系统中的治疗效果。
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