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Here we show that genetic ablation of the triglyceride and phospholipid lipase\n                    <jats:italic>Ddhd2<\/jats:italic>\n                    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\n                    <jats:italic>Ddhd2<\/jats:italic>\n                    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 \u03b2-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\n                    <jats:italic>DDHD2<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1038\/s42255-025-01367-x","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T09:03:43Z","timestamp":1759223023000},"page":"2117-2141","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["DDHD2 provides a flux of saturated fatty acids for neuronal energy and function"],"prefix":"10.1038","volume":"7","author":[{"given":"Saber 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