DDHD2 provides a flux of saturated fatty acids for neuronal energy and function PMID: 41028912

ADC Targets in Oncology

2026-04-10

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

Nat Metab. 2025 Sep 30. doi: 10.1038/s42255-025-01367-x.

Saber H Saber ¹ ² ³ , Nyakuoy Yak ¹ ² , Xuan Ling Hilary Yong ² ⁴ , Yih Tyng Bong ⁵ ⁶ ⁷ , Hannah Leeson ¹ , Chuan-Yang Dai ² ⁴ , Tobias Binder ¹ , Siyuan Lu ¹ , Reshinthine Purushothaman ¹ , An-Sofie Lenaerts ⁵ ⁶ ⁷ , Leonardo Almeida-Souza ⁵ ⁶ ⁷ , Lidiia Koludarova ⁵ , Safak Er ⁸ , Irena Hlushchuk ⁸ , Arnaud Gaudin ² , Sachin Singh ⁹ , Tuula A Nyman ⁹ , Jeffrey R Harmer ¹ ¹⁰ , Steven Zuryn ² ⁴ ¹¹ , Ernst Wolvetang ¹ , Gert Hoy Talbo ¹ , Mikko Airavaara ⁸ , Brendan J Battersby ⁵ , Ashley J van Waardenberg ¹² , Victor Anggono ² ⁴ ¹¹ , Giuseppe Balistreri ⁵ ¹³ , Merja Joensuu ¹⁴

Affiliations

1. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
2. Queensland Brain Institute, Faculty of Health, Medicine and Behavioural Sciences, The University of Queensland, Brisbane, Queensland, Australia.
3. Zoology and Entomology Department, Faculty of Science, Assiut University, Assiut, Egypt.
4. Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Queensland, Australia.
5. Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
6. Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
7. Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.
8. Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
9. Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.
10. Centre for Advanced Imaging, The University of Queensland, Brisbane, Queensland, Australia.
11. NHMRC Centre for Research Excellence in Mechanisms in NeuroDegeneration - Alzheimer's Disease (MIND-AD CRE), Brisbane, Queensland, Australia.
12. i-Synapse PTY LTD, Cairns, Queensland, Australia.
13. Department of Virology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
14. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia. [email protected].

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.