biostudies-literatureSaber SHAcademy of FinlandNorges ForskningsrådAcademy of Finland (Suomen Akatemia)Department of Education and Training | Australian Research Council (ARC)Department of Education and Training | Australian Research CouncilNorges Forskningsråd (Research Council of Norway)Sigrid Juséliuksen SäätiöEC | Horizon 2020 Framework ProgrammeSigrid Juselius Foundation, National Ataxia Foundation, Lindsey Flynt, Hereditary Neuropathy Foundation, Research Council of Finland.EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)2117-2141https://www.ebi.ac.uk/biostudies/studies/S-EPMC12552131biostudies-literatureUnknown7(10)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 actiNature metabolismDDHD2 provides a flux of saturated fatty acids for neuronal energy and function.PMC12552131101057553295910335527FT220100485Almeida-Souza LGaudin ABalistreri GSaber SHAnggono VBong YTLenaerts ASvan Waardenberg AJKoludarova LSingh SHarmer JRLeeson HBattersby BJBinder TEr SYak NWolvetang ENyman TAZuryn SPurushothaman RHlushchuk IYong XLHJoensuu MAiravaara MTalbo GHLu SDai CYfalseDDHD2 provides a flux of saturated fatty acids for neuronal energy and function.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 acti2025-01-01T00:00:00Z2025 Oct2026-07-15T12:14:20.585Z2026-07-04T03:13:10.446ZS-EPMC125521314102891210.1038/s42255-025-01367-x