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DDHD2 provides a flux of saturated fatty acids for neuronal energy and function

Saber, Saber H., Yak, Nyakuoy, Yong, Xuan Ling Hilary, Bong, Yih Tyng, Leeson, Hannah, Dai, Chuan-Yang, Binder, Tobias, Lu, Siyuan, Purushothaman, Reshinthine, Lenaerts, An-Sofie, Almeida-Souza, Leonardo, Koludarova, Lidiia, Er, Safak, Hlushchuk, Irena, Gaudin, Arnaud, Singh, Sachin, Nyman, Tuula A., Harmer, Jeffrey R., Zuryn, Steven, Wolvetang, Ernst, Talbo, Gert Hoy, Airavaara, Mikko, Battersby, Brendan J., van Waardenberg, Ashley J., Anggono, Victor, Balistreri, Giuseppe, Joensuu, Merja·2025·Nature Metabolism
DOI 10.1038/s42255-025-01367-xPMC PMC12552131

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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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Metadata

Authors
Saber, S. H., Yak, N., Yong, X. L. H., Bong, Y. T., Leeson, H., Dai, C.-Y., Binder, T., Lu, S., Purushothaman, R., Lenaerts, A.-S., Almeida-Souza, L., Koludarova, L., Er, S., Hlushchuk, I., Gaudin, A., Singh, S., Nyman, T. A., Harmer, J. R., Zuryn, S., Wolvetang, E., Talbo, G. H., Airavaara, M., Battersby, B. J., van Waardenberg, A. J., Anggono, V., Balistreri, G., & Joensuu, M.
ORCID
Venue
Nature Metabolism
Publisher
Springer Science and Business Media LLC
Published
2025-09-30
Volume
7
Issue
10
Pages
2117-2141
ISSN
2522-5812
DOI
10.1038/s42255-025-01367-x
PMC
PMC12552131
Cited by
44
References
10
Language
en
Licence
Funders
  • Norges Forskningsråd (295910)
  • Department of Education and Training | Australian Research Council (FT220100485)
  • Sigrid Juséliuksen Säätiö
  • Academy of Finland (335527)
  • Sigrid Juselius Foundation, National Ataxia Foundation, Lindsey Flynt, Hereditary Neuropathy Foundation, Research Council of Finland.
  • EC | Horizon 2020 Framework Programme (101057553)

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