ArticleProceedings of the National Academy of Sciences of the United States of America2023
Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it, 111 citations in OpenAlex.
- The effect of repetitive transcranial magnetic stimulation on immediate and long-term cognitive functions in Alzheimer's dementia and mild cognitive impairment: a meta-analysis.Journal of neuroengineering and rehabilitation · 2025Pooled it
- Brain mitochondria as key drivers of cognition and behaviour.Nature reviews. Neuroscience · 2026Review
- TSPO Regulates TLR4-Mediated Inflammation Through Calcium Homeostasis and Immunometabolic Adaptation.International journal of molecular sciences · 2026Article
- Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.Molecular neurobiology · 2026Review
- Role Shift of Glial Cells from Physiology to Pathology in Alzheimer's Disease: The Regulatory Impact of Exercise.Neuroscience bulletin · 2026Review
- Bioenergetic-active hybrid nanovesicles empower tumor associated macrophages phagocytosis for cancer immunotherapy.Materials today. Bio · 2026Article
- Microglial Activation Under Hypoxic Conditions in Early Alzheimer's Disease: Can Natural SIRT1 Activators Be Therapeutic Allies in the Inflammation-Energy Axis?Phytotherapy research : PTR · 2026Review
- Glycolysis: The Bridge Between Cellular Interaction and Alzheimer's Disease.Biomolecules · 2026Review
- The Converging Effects of Different Categories of Antidepressants on the Brain: A Systematic Meta-Analysis of Public Transcriptional Profiling Data from the Hippocampus and Cortex.bioRxiv : the preprint server for biology · 2026Article
- Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.Nature aging · 2026Article
- Metabolic Reprogramming of Microglia in Neuroinflammation and Depression.International journal of molecular sciences · 2026Review
- Advancements in the Study of Missense Mutations in ABCA7 in Alzheimer's Disease.Journal of molecular neuroscience : MN · 2026Review
- Dynamic transcriptomic remodeling in grafted human neural progenitor cells uncovers mechanisms for vision preservation in a rat model of retinitis pigmentosa.Nature communications · 2026Article
- Therapeutic Targeting of Microglial Hexokinase-2 Recalibrates Inflammasome Activation and Improves Functional Recovery After Traumatic Brain Injury.bioRxiv : the preprint server for biology · 2026Article
- Microglial Fkbp5 Impairs Post-Stroke Vascular Integrity and Regeneration by Promoting Yap1-Mediated Glycolysis and Oxidative Phosphorylation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Role of Microglial Dysfunction in Parkinson's Disease: From Multifactorial Causes to Neurodegeneration.Neuroscience bulletin · 2026Review
- Primary Human Reactive Microglia Display Mitochondrial Dysfunction and Metabolic Imbalance Upon Lipopolysaccharide Exposure.Neurochemical research · 2026Article
- Propionibacterium acnes evades microbicidal phagocytosis by inhibiting the mitochondrial biogenesis of nucleus pulposus cells.The FEBS journal · 2026Article
- Microglia in autism spectrum disorder: heterogeneity, immunometabolism, and synapse-related pathways.Frontiers in immunology · 2026Review
- Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.Frontiers in chemistry · 2026Review
22 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimer's disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimer's beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.
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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.