Cited by 12Parkinson's Disease Mechanisms and TreatmentsMitochondrial Function and PathologyNuclear Receptors and Signaling

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

Walecha, Vaishali, Luthra, Pratibha M.·2025·Neurochemical Research

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.

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Crossref · 10.1007/s11064-025-04559-9

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Research works printed but not linked: 6

  1. Zade A (2025) Glial metabolism in neurodegenerative disorders: bridging pathophysiology and therapeutics. J Internal Med Pharmacol 2(01):01–12
  2. Bantle CM, Hirst WD, Weihofen A, Shlevkov E (2021) Mitochondrial dysfunction in astrocytes: A role in Parkinson’s disease? Front Cell Dev Biol 8:608026 · DOI · Paper page
  3. Bhatti JS, Bhatti GK, Reddy PH (2017) Mitochondrial dysfunction and oxidative stress in metabolic disorders — a step towards mitochondria-based therapeutic strategies. Biochim Biophys Acta (BBA) Mol Basis of Dis 1863(5):1066–1077. https://doi.org/10.1016/j.bbadis.2016.11.010 · DOI · Paper page
  4. Iovino L, Tremblay ME, Civiero L (2020) Glutamate-induced excitotoxicity in Parkinson’s disease: the role of glial cells. J Pharmacol Sci 144(3):151–164. https://doi.org/10.1016/j.jphs.2020.07.011 · DOI
  5. Henrich MT, Oertel WH, Surmeier DJ, Geibl FF (2023) Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential. Mol Neurodegener 18(1):83. https://doi.org/10.1186/s13024-023-00676-7 · DOI
  6. Bantle CM, Hirst WD, Weihofen A, Shlevkov E (2020) Mitochondrial dysfunction in astrocytes: a role in Parkinson’s disease? Front Cell Dev Biol 8:608026. https://doi.org/10.3389/fcell.2020.608026 · DOI · Paper page

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Authors
Walecha, V., & Luthra, P. M.
Affiliations
University of Delhi (IN)
Corresponding author
Luthra, Pratibha M.
Venue
Neurochemical Research
Published
2025-10
Volume
50
Issue
5
Pages
317-317
ISSN
  • 0364-3190 (ISSN-L)
  • 1573-6903
OpenAlex
W4414809925
Cited by
12
References
188
Citations by year
2026: 11 · 2025: 1
FWCI
2.14
Type
journal article
Language
en
Open access
closed
Locations
  • Neurochemical Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, mitochondrial quality control, mitophagy, alpha-synuclein aggregation, oxidative stress, ferroptosis, neuroinflammation, glutamate regulation, metabolic coupling, metabolic reprogramming, mitochondrial transfer, dopaminergic neuron loss, neuroprotection
MeSH terms
Animals, Astrocytes, Humans, Mitochondria, Neurons, Parkinson Disease, Oxidative Stress, Dopaminergic Neurons

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