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<p>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 <i>Ddhd2</i> 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 <i>Ddhd2</i> 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 <i>DDHD2</i> mutations.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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

摘要

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.