ArticleGlia2019
Astrocyte-specific deletion of the mitochondrial m-AAA protease reveals glial contribution to neurodegeneration.
Article in Glia, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 48 citations in OpenAlex.
- Microglial mitophagy as an immunometabolic checkpoint in alzheimer's disease: linking mitochondrial quality control to neuroinflammation.Journal of neuroinflammation · 2026Review
- Mitochondrial Dysfunction at the Crossroads of Necroptosis: Mechanisms, Molecular Mediators, and Therapeutic Opportunities.Journal of cellular and molecular medicine · 2026Review
- Information flow drives localized morphological differences across neuronal and glial cell types.Frontiers in computational neuroscience · 2026Article
- Novel hypothesis and therapeutic interventions for irritable bowel syndrome: interplay between metal dyshomeostasis, gastrointestinal dysfunction, and neuropsychiatric symptoms.Molecular and cellular biochemistry · 2025Review
- Astroglial modulation of synaptic function in the non-demyelinated cerebellar cortex is dependent on MyD88 signaling in a model of toxic demyelination.Journal of neuroinflammation · 2025Article
- Bioenergetic-related gene expression in the hippocampus predicts internalizing vs. externalizing behavior in an animal model of temperament.Frontiers in molecular neuroscience · 2025Article
- Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.Molecular neurobiology · 2024Review
- Regulation of blood-brain barrier integrity byScience advances · 2024Article
- Review
- Aberrant CHCHD2-associated mitochondriopathy in Kii ALS/PDC astrocytes.Acta neuropathologica · 2024Article
- Ucp4 Knockdown of Cerebellar Purkinje Cells Induces Bradykinesia.Molecular neurobiology · 2024Article
- Aging, Neurodegenerative Disorders, and Cerebellum.International journal of molecular sciences · 2024Review
- Role of Necroptosis, a Regulated Cell Death, in Seizure and Epilepsy.Neurochemical research · 2024Review
- Cell-Type-Specific Mitochondrial Quality Control in the Brain: A Plausible Mechanism of Neurodegeneration.International journal of molecular sciences · 2023Review
- Neuronal branching is increasingly asymmetric near synapses, potentially enabling plasticity while minimizing energy dissipation and conduction time.Journal of the Royal Society, Interface · 2023Article
- The Relationships Among Metal Homeostasis, Mitochondria, and Locus Coeruleus in Psychiatric and Neurodegenerative Disorders: Potential Pathogenetic Mechanism and Therapeutic Implications.Cellular and molecular neurobiology · 2023Review
- Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes.The Journal of cell biology · 2023Article
- How axon and dendrite branching are guided by time, energy, and spatial constraints.Scientific reports · 2022Article
- Dynamic instability of dendrite tips generates the highly branched morphologies of sensory neurons.Science advances · 2022Article
- Age-Associated Glia Remodeling and Mitochondrial Dysfunction in Neurodegeneration: Antioxidant Supplementation as a Possible Intervention.Nutrients · 2022Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial dysfunction causes neurodegeneration but whether impairment of mitochondrial homeostasis in astrocytes contributes to this pathological process remains largely unknown. The m-AAA protease exerts quality control and regulatory functions crucial for mitochondrial homeostasis. AFG3L2, which encodes one of the subunits of the m-AAA protease, is mutated in spinocerebellar ataxia SCA28 and in infantile syndromes characterized by spastic-ataxia, epilepsy and premature death. Here, we investigate the role of Afg3l2 and its redundant homologue Afg3l1 in the Bergmann glia (BG), radial astrocytes of the cerebellum that have functional connections with Purkinje cells (PC) and regulate glutamate homeostasis. We show that astrocyte-specific deletion of Afg3l2 in the mouse leads to late-onset motor impairment and to degeneration of BG, which display aberrant morphology, altered expression of the glutamate transporter EAAT2, and a reactive inflammatory signature. The neurological and glial phenotypes are drastically exacerbated when astrocytes lack both Afg31l and Afg3l2, and therefore, are totally depleted of the m-AAA protease. Moreover, mitochondrial stress responses and necroptotic markers are induced in the cerebellum. In both mouse models, targeted BG show a fragmented mitochondrial network and loss of mitochondrial cristae, but no signs of respiratory dysfunction. Importantly, astrocyte-specific deficiency of Afg3l1 and Afg3l2 triggers secondary morphological degeneration and electrophysiological changes in PCs, thus demonstrating a non-cell-autonomous role of glia in neurodegeneration. We propose that astrocyte dysfunction amplifies both neuroinflammation and glutamate excitotoxicity in patients carrying mutations in AFG3L2, leading to a vicious circle that contributes to neuronal death.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.