The Mitochondrial-Astrocyte-Neuron Triad Hypothesis in Parkinson’s Disease: A Toxic Feedback Loop of Metabolism, Aggregation, and Oxidative Stress

IF 3.8 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Vaishali Walecha, Pratibha M. Luthra
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引用次数: 0

Abstract

The medical field has spent many years investigating Parkinson's disease (PD), primarily focusing on its main pathogenic feature, dopaminergic neuronal degeneration. Recent studies indicate that PD develops through a complex pathogenic model that links mitochondria to astrocytes and neurons, creating a destructive metabolic loop, a protein aggregation cycle, and oxidative stress. This review examines how mitochondria integrate with astrocytes and neurons in the “triad hypothesis,” offering a multifaceted perspective on PD progression. Despite being previously overlooked, we have observed that astrocytic mitochondria play a central role in maintaining neuroprotection and homeostasis. Given that, dysfunctional mitochondria in astrocytes and neurons lead to metabolic failure, compromised glutamate regulation, while also enhancing α-synuclein aggregation, amplifying neuroinflammation, ferroptotic vulnerability and oxidative stress. Henceforth, this report discusses current insights into astrocyte–neuron metabolic coupling, mitochondrial quality control, and lipid redox imbalance, highlighting the role of astrocytic mitochondria as a strong therapeutic strategy. We discuss experimental and translational approaches that aim to restore triad integrity, including mitophagy enhancement, metabolic reprogramming, mitochondrial transfer, and astrocyte-to-neuron reprogramming. By positioning astrocytic mitochondria at the core of PD pathogenesis, this review advocates novel interventions focused on glial metabolic resilience. This integrated approach addresses three major pathogenic axes. It offers promising potential for disease modification and developing effective therapeutics beyond symptomatic dopamine replacement to correct neurodegenerative conditions.

Graphical Abstract

帕金森病的线粒体-星形细胞-神经元三联假说:代谢、聚集和氧化应激的毒性反馈循环
医学界对帕金森病(PD)进行了多年的研究,主要集中在其主要致病特征多巴胺能神经元变性上。最近的研究表明,帕金森病是通过一个复杂的致病模型发展起来的,该模型将线粒体与星形胶质细胞和神经元联系起来,创造了一个破坏性的代谢循环、一个蛋白质聚集循环和氧化应激。这篇综述探讨了线粒体如何在“三合一假说”中与星形胶质细胞和神经元整合,为帕金森病的进展提供了一个多方面的视角。尽管以前被忽视,我们已经观察到星形细胞线粒体在维持神经保护和体内平衡中起着核心作用。因此,星形胶质细胞和神经元线粒体功能失调导致代谢衰竭,谷氨酸调节受损,同时α-突触核蛋白聚集增强,神经炎症、铁致易感性和氧化应激增强。因此,本报告讨论了目前对星形细胞-神经元代谢偶联、线粒体质量控制和脂质氧化氧化不平衡的见解,强调了星形细胞线粒体作为一种强有力的治疗策略的作用。我们讨论了旨在恢复三合一完整性的实验和转化方法,包括线粒体自噬增强、代谢重编程、线粒体转移和星形胶质细胞到神经元的重编程。通过将星形细胞线粒体定位于帕金森病发病机制的核心,本综述提倡以神经胶质代谢弹性为重点的新干预措施。这种综合方法涉及三个主要的致病轴。它为疾病改造和开发有效的治疗方法提供了有希望的潜力,而不是症状性多巴胺替代来纠正神经退行性疾病。图形抽象
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来源期刊
Neurochemical Research
Neurochemical Research 医学-神经科学
CiteScore
7.70
自引率
2.30%
发文量
320
审稿时长
6 months
期刊介绍: Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.
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