Fat fuels our brains in new AIBN discovery

New research from the Australian Institute for Bioengineering and Nanotechnology (AIBN) has revealed that neurons in the brain use fats for energy, challenging decades of scientific thinking and opening the door to new treatments for neurological disease.

For years, scientists believed that healthy neurons, the brain’s communication cells, relied solely on glucose and its metabolites to power their activity. But a team led by AIBN’s Dr Merja Joensuu has now shown that certain fats are essential for keeping these cells functioning.

“The brain requires a lot of energy to sustain neuronal communication, and it is widely believed that this energy comes from our diet,” Dr Joensuu said.

“To our surprise our research showed that this is not entirely true. Neurons create small fat molecules - called fatty acids - from within, as part of the brain’s own fat metabolism. These fats are used to generate the energy needed to keep brain cells functioning.

“We’ve discovered that these fatty acids play such a significant role in feeding the neuron the energy it needs, that without them, the cells lose power and eventually stop working.”

The study centred on a gene called DDHD2, which enables neurons to break down fats and produce fatty acids.

“When DDHD2 is mutated, as seen in people with HSP54, a rare form of hereditary spastic paraplegia, neurons lose access to those essential fatty acids, leading to energy failure and progressive neurological decline,” Dr Joensuu said.

“Our research suggests that in people with HSP54, this fatty acid imbalance and energy loss may be the underlying cause to muscle stiffness, trouble walking, and poor coordination.

“Many also experience cognitive delays and developmental challenges as brain cells gradually lose the ability to function and communicate.”

AIBN researchers Nyakuoy Yak and Saber Abd Elkader worked closely with Dr Joensuu to examine how the gene functions in healthy neurons and what happens when it doesn’t.

“DDHD2 acts like a switch for this fat-powered energy pathway,” Dr Joensuu said.

“When it’s not working properly, neurons can’t access the fats they need, and they start to run out of energy.”

The team discovered that under normal conditions, around 20% of a neuron’s energy, and even more during high activity, comes from this fat-burning process.

The consequences of losing this energy pathway went beyond low energy.

“These neurons weren’t just running low on fuel, they were breaking down in other ways,” Dr Joensuu said.

“We saw problems with communication, protein processing, and even how the cells maintained their structure.”

The breakthrough came when the team added activated forms of the missing fatty acids, specifically myristic, palmitic, and stearic acids, back into affected brain cells.

These fats restored energy levels and reversed the neuronal defects. Even in neurons with faulty DDHD2, energy production restarted, mitochondria began functioning again, and other key processes returned to normal.

“It was incredibly encouraging to see how effective the treatment was in the lab,” Dr Joensuu said.

While there is currently no cure for HSP54, these findings open a new path toward therapies.

The team believes this fat-fuelled energy pathway could also be relevant for other neurological diseases where energy failure plays a role including dementias and metabolic brain diseases.

“This marks the first time we’ve seen a fat-based therapy show this kind of promise for HSP54,” Dr Joensuu said.

“It suggests fats don’t just fuel the brain - they help keep its complex machinery running smoothly.”

The team now hopes their discovery will lead to new treatment strategies and a deeper understanding of how neurons survive, struggle, and potentially recover.

The research was published in Nature Metabolism, and co-authored by 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 and Merja Joensuu.

Collaborators included researchers from UQ’s Queensland Brain Institute, the University of Helsinki, the University of Oslo, Assiut University, and omics data analysis firm i-Synapse.

This research wouldn’t have been possible without the support of donors like Bruce and Anthea McBryde, whose generosity is helping drive forward life-changing discoveries in neurological disease.