ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2020
Mitochondrial Dysfunction Combined with High Calcium Load Leads to Impaired Antioxidant Defense Underlying the Selective Loss of Nigral Dopaminergic Neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
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- Chronic Methamphetamine Administration Increases Mitochondrial Density and Impairs Mitochondrial Function in the Substantia Nigra Pars Compacta.Journal of neurochemistry · 2026Article
- Curcumin Rescues Oxidative Stress-Induced Impairment of PINK1/Parkin Pathway-Mediated Mitophagy in APOE4-Expressing Astrocytes.Molecular neurobiology · 2026Article
- Magnetoreceptive CRY/MagR complexes: linking circadian redox signalling to protein aggregation in Alzheimer's and Parkinson's disease.ADMET & DMPK · 2026Review
- Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson's disease.Disease models & mechanisms · 2026Article
- Sleep deprivation and risk for Parkinson's disease: evidence and therapeutic implications.Journal of neurology · 2025Review
- Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration.bioRxiv : the preprint server for biology · 2025Article
- A comprehensive review of natural compounds and their structure-activity relationship in Parkinson's disease: exploring potential mechanisms.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice.The European journal of neuroscience · 2024Article
- Ablation of Mitochondrial RCC1-L Induces Nigral Dopaminergic Neurodegeneration and Parkinsonian-like Motor Symptoms.bioRxiv : the preprint server for biology · 2024Article
- Selenium-SelK-GPX4 axis protects nucleus pulposus cells against mechanical overloading-induced ferroptosis and attenuates senescence of intervertebral disc.Cellular and molecular life sciences : CMLS · 2024Article
- Deep learning-based image analysis identifies a DAT-negative subpopulation of dopaminergic neurons in the lateral Substantia nigra.Communications biology · 2023Article
- PINK1 and Parkin regulate IPNature communications · 2023Article
- Glutamine supplementation reverses manganese neurotoxicity by eliciting the mitochondrial unfolded protein response.iScience · 2023Article
- Development, wiring and function of dopamine neuron subtypes.Nature reviews. Neuroscience · 2023Review
- Effects of Apamin on MPPInternational journal of molecular sciences · 2022Article
- Upregulation of CaMolecular neurodegeneration · 2022Article
- Intrauterine exposure to oxidative stress induces caspase-1-dependent enteric nerve cell pyroptosis.Pediatric surgery international · 2022Article
- Microglia as the Critical Regulators of Neuroprotection and Functional Recovery in Cerebral Ischemia.Cellular and molecular neurobiology · 2022Review
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.
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