Summary: New research shows that neurons are not exclusively dependent on glucose for energy; they can also generate and burn fats. When neuronal energy demand rises, cells can produce their own fatty acids by recycling internal membranes and lipid stores — a process that relies on the enzyme DDHD2. Defects in DDHD2 underlie the neurodegenerative condition Hereditary Spastic Paraplegia 54 (HSP54), but supplying specific fatty acids restored energy production and neuronal function in laboratory-grown neurons within 48 hours, pointing to a promising therapeutic direction.
This discovery challenges long-standing assumptions about brain metabolism and identifies a direct biochemical pathway that supports mitochondrial ATP production in neurons through β‑oxidation of endogenous long‑chain saturated fatty acids.
Key Facts:
- Fat-fueled neurons: Neurons can oxidize long‑chain saturated fatty acids to generate ATP, not just rely on glucose.
- Role of DDHD2: DDHD2 is a triglyceride and phospholipid lipase required for releasing long‑chain saturated free fatty acids (myristic, palmitic and stearic acids) in an activity‑dependent manner.
- Clinical relevance: Loss of DDHD2 impairs mitochondrial respiration and ATP synthesis, causing early and progressive motor and cognitive symptoms in HSP54; targeted fatty acid supplementation rescued energy production and synaptic function in cultured neurons.
Research teams: Scientists from the University of Queensland (Australia) and the University of Helsinki (Finland) collaborated on this work, combining cellular, biochemical and imaging approaches to uncover how neurons meet high ATP demands.
A discovery that could change patient outcomes
Hereditary Spastic Paraplegia 54 (HSP54) is caused by mutations that render DDHD2 nonfunctional. In cells lacking DDHD2, researchers observed reduced mitochondrial respiration and lower ATP synthesis despite an increase in glycolysis, indicating that glucose metabolism alone could not compensate. The underlying biochemical deficit was a depletion of long‑chain saturated free fatty acids normally generated by DDHD2 activity. This shortfall impairs neuronal energy supply, membrane trafficking and synaptic function, producing the progressive motor and cognitive symptoms seen in patients.
Importantly, the researchers demonstrated that supplying activated forms of those saturated fatty acids — saturated fatty acyl‑CoA species — restored mitochondrial energy production in DDHD2‑deficient neurons. When used together, these supplements also rescued defects in membrane trafficking, synaptic activity and protein homeostasis. These effects appeared rapidly: cultured neurons showed recovery of energy metrics and functional activity within 48 hours of treatment.
“This is a real game‑changer,” said Dr Merja Joensuu, who initiated and led the study at the Australian Institute for Bioengineering and Nanotechnology. “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.”
Translational steps and future development
Following these cellular findings, the research teams are advancing toward pre‑clinical testing to determine whether fatty acid‑based therapies are safe and effective in animal models. Those studies are an essential step before considering clinical trials in people. The investigators also plan to use non‑invasive brain imaging technologies to monitor metabolic changes and to speed up therapy development.
Dr Giuseppe Balistreri from the University of Helsinki emphasized the broader implications: “This breakthrough doesn’t just rewrite the textbooks, it could transform lives.” The teams will explore whether restoring neuronal lipid flux can benefit other neurodegenerative or metabolic brain disorders where energy supply is compromised.
Key questions and answers
A: Neurons can oxidize long‑chain saturated fatty acids for mitochondrial ATP production and can generate these fatty acids from internal lipid stores in an activity‑dependent manner.
A: DDHD2 acts as a lipase that releases long‑chain saturated free fatty acids required for mitochondrial β‑oxidation. Loss of DDHD2 reduces these substrates and impairs neuronal energy production and function.
A: Supplying activated saturated fatty acids restored mitochondrial respiration and rescued synaptic and trafficking defects in cultured DDHD2‑deficient neurons, suggesting a potential therapeutic approach for HSP54 and possibly other disorders with compromised neuronal energy metabolism.
About this research
Author: Pia Purra
Source: University of Helsinki
Contact: Pia Purra, University of Helsinki
Image: Credit to Neuroscience News
Original research: Open access. Article title: “DDHD2 provides a flux of saturated fatty acids for neuronal energy and function” by Giuseppe Balistreri. Published in Nature Metabolism.
Abstract (summary)
DDHD2 provides a flux of saturated fatty acids for neuronal energy and function
Although fatty acids fuel mitochondrial ATP production in many tissues, neurons were long thought to depend almost exclusively on glucose. This study shows that genetic deletion of the triglyceride and phospholipid lipase Ddhd2 impairs mitochondrial respiration and ATP synthesis in cultured neurons despite elevated glycolysis. The defect stems from reduced levels of long‑chain saturated free fatty acids — notably myristic, palmitic and stearic acids — that are normally released in an activity‑dependent manner by Ddhd2.
Blocking mitochondrial fatty acid import in wild‑type neurons produced similar reductions in respiration and ATP generation. Treatment of Ddhd2 knockout neurons with saturated fatty acyl‑CoA compounds restored mitochondrial energy production. Combined treatment also corrected defects in membrane trafficking, synaptic function and protein homeostasis. These findings reveal that neurons perform β‑oxidation of endogenous long‑chain saturated fatty acids to meet ATP demands and identify a potential therapeutic strategy for HSP54 caused by DDHD2 mutations.