ArticleNature metabolism2025
DDHD2 provides a flux of saturated fatty acids for neuronal energy and function.
Article in Nature metabolism, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed.
- Lipid-fuelled synaptic plasticity: integrating membrane turnover, β-oxidation, and protein lipidation.The EMBO journal · 2026Review
- β-Hydroxybutyrate Maintains Energetically Demanding Neural Functions During Exogenous Glucose Deprivation.Cellular and molecular neurobiology · 2026Article
- APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.Nature genetics · 2026Article
- Article
- Age-dependent changes in lipid droplet distribution and vascularization in naked mole rat vs. mouse hippocampus.GeroScience · 2026Article
- Mitochondrial molecular diversity in the brain.Current opinion in neurobiology · 2026Review
- Neurons run on fat.npj metabolic health and disease · 2026Article
- Brain mitochondria as key drivers of cognition and behaviour.Nature reviews. Neuroscience · 2026Review
- Reduction of Lipid Droplets Modulates the Injury Response and Enhances CNTF-Induced Axon Regeneration Following Optic Nerve Crush.Molecular neurobiology · 2026Article
- Rewiring Lipid Metabolism: PINK1 as a Central Regulator of Mitochondrial Homeostasis in Parkinson's Disease.International journal of molecular sciences · 2026Review
- Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.bioRxiv : the preprint server for biology · 2026Article
- Symptom impact and safety of ketogenic therapy in adults with anorexia nervosa: a feasibility trial.Communications medicine · 2026Article
- Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.bioRxiv : the preprint server for biology · 2026Article
- Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis.Nature metabolism · 2026Article
- Metabolic permissiveness: how tissue context shapes cancer.Genes & development · 2026Review
- Signaling roles for astrocytic lipid metabolism in brain function.EMBO reports · 2026Review
- Exploring biomarkers of mitochondrial dynamics in polycystic ovary syndrome and the effect of mesenchymal stem cell transplantation on ovarian mitochondria.Journal of ovarian research · 2026Article
- Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?Frontiers in aging neuroscience · 2026Review
- A Lipid Road to Neuroimmunology: Fatty Acids Linking Immune and Nervous Systems.Neuroimmunomodulation · 2026Review
- Modeling pathogenesis and progression of metabolic dysfunction-associated steatotic liver disease and therapeutic drug screening using hESC-derived mature polarized hepatocyte organoids.Stem cell research & therapy · 2025Article
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Authors and funding
27 authors.
Funding
Abstract
Although fatty acids support mitochondrial ATP production in most tissues, neurons are believed to rely exclusively on glucose for energy. Here we show that genetic ablation of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons, despite increased glycolysis. This defect arises from reduced levels of long-chain saturated free fatty acids, particularly myristic, palmitic and stearic acids, normally released in an activity-dependent manner by Ddhd2. Inhibition of mitochondrial fatty acid import in wild-type neurons similarly reduced mitochondrial respiration and ATP production. Saturated fatty acyl-coenzyme A treatment restored mitochondrial energy production in Ddhd2 knockout neurons. When provided in combination, these activated fatty acyl-CoA supplements also rescued defects in membrane trafficking, synaptic function and protein homeostasis. These findings uncover that neurons perform β-oxidation of endogenous long-chain free fatty acids to meet ATP demands and reveal a potential therapeutic strategy for hereditary spastic paraplegia 54 caused by DDHD2 mutations.
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