Researchers in Australia and Finland report that neurons can fuel themselves with fat as well as sugar, challenging long‑held assumptions about brain energy. The discovery, published in Nature Metabolism, links a lipid‑processing enzyme to a rare hereditary spastic paraplegia and suggests that targeted fatty acid supplements may restore cellular energy in laboratory models.
Scientists at the University of Queensland and the University of Helsinki have shown that neurons generate ATP by burning long‑chain saturated fatty acids, overturning the view that neurons rely exclusively on glucose. The pathway depends on DDHD2, a triglyceride/phospholipid lipase that releases saturated free fatty acids in an activity‑dependent manner. (pubmed.ncbi.nlm.nih.gov)
When DDHD2 is mutated—as in Hereditary Spastic Paraplegia 54 (also known as SPG54)—neuronal respiration falters despite heightened glycolysis, pointing to an energy shortfall linked to reduced myristic, palmitic, and stearic acids. Clinically, SPG54 is typically early‑onset and progressive, with motor impairment often accompanied by cognitive involvement. (pubmed.ncbi.nlm.nih.gov)
In laboratory models, providing activated forms of these fatty acids (acyl‑CoAs) restored mitochondrial ATP production and rescued defects in synaptic function, membrane trafficking, and protein homeostasis. University communications add that damaged neurons regained energy production and activity within about 48 hours after fatty acid supplementation. (pubmed.ncbi.nlm.nih.gov)
“This is a real game‑changer,” said Dr. Merja Joensuu of the Australian Institute for Bioengineering and Nanotechnology, who led the study. “We’ve shown that healthy neurons rely on fats for fuel, and when this pathway fails in conditions like HSP54, it may be possible to repair the damage and reverse the neuropathologies.” (sciencedaily.com)
The team says next steps include testing the safety and effectiveness of fatty‑acid–based approaches in preclinical models, and pursuing non‑invasive brain imaging to speed development. “We will continue the exciting collaboration with new non‑invasive technologies to image the brain and therefore aid a faster development of the potential therapy,” said Dr. Giuseppe Balistreri of the University of Helsinki. (eurekalert.org)
The peer‑reviewed study, “DDHD2 provides a flux of saturated fatty acids for neuronal energy and function,” was published online September 30, 2025 (Nature Metabolism, 7[10]: 2117–2141; doi: 10.1038/s42255‑025‑01367‑x). (pubmed.ncbi.nlm.nih.gov)