Summary: Fatigue is one of the most disabling and hardest-to-treat symptoms of major depressive disorder (MDD). New research points to a biological cause: a breakdown in ATP bioenergetics that leaves cells unable to meet increased energy demand.
Researchers measured the brain and blood “energy currency” molecule adenosine triphosphate (ATP) in young adults with and without depression. They found that cells from people with MDD showed unusually high ATP production at rest but were unable to increase ATP output when challenged, suggesting early mitochondrial strain that may underlie persistent fatigue, slowed thinking, and low motivation.
Key Findings
- Resting overdrive: Brain and blood cells from young adults with depression produced more ATP at rest than cells from control participants, indicating a system already operating near its limit.
- Impaired response to stress: Despite higher resting ATP, these cells showed a diminished capacity to raise energy production under metabolic stress or increased cognitive demand.
- Shared biomarker in brain and blood: For the first time, the same ATP-related pattern associated with fatigue was observed both in the brain and in peripheral blood cells, opening the possibility of an objective blood-based biomarker for MDD-related fatigue.
Source: University of Queensland
New approach to early diagnosis and treatment
A team led by researchers at the University of Queensland (UQ), in collaboration with the University of Minnesota, examined ATP concentration and production rate in the brain and peripheral blood mononuclear cells (PBMCs) from young people diagnosed with MDD and from healthy controls. The goal was to identify molecular mechanisms that might explain the persistent fatigue seen early in the course of depression and to find potential targets for earlier, more effective intervention.
Associate Professor Susannah Tye of UQ’s Queensland Brain Institute said this is the first study to identify a consistent ATP signature linked to fatigue in both the brain and bloodstream of young people with major depressive disorder.
“These results indicate that some depressive symptoms may stem from fundamental changes in how brain and blood cells produce and manage energy,” Dr Tye explained. Fatigue is common in MDD and can be especially difficult to treat. Finding a biological basis for this symptom could speed diagnosis and guide more targeted treatments early in illness progression.
In the study, collaborators at the University of Minnesota collected blood samples and brain scans from 18 participants aged 18–25 diagnosed with MDD. The UQ team analyzed these samples and compared them with measurements from non-depressed control participants.
QBI researcher Dr. Roger Varela reported that cells from participants with depression produced more ATP while at rest but showed a lower capacity to boost ATP production when mitochondrial function was challenged. “This pattern suggests that cells may be compensating early on, working harder at baseline, which could exhaust their reserve and lead to longer-term dysfunction,” he said.
This finding runs counter to the simple expectation that energy production would always be lower in depression. Instead, it points to a compensatory response in early-stage illness where mitochondria push to maintain baseline function but lack flexibility to handle additional demand—an energetic bottleneck that can manifest as profound tiredness, reduced drive, and slowed cognition.
Dr. Varela emphasized that these results help underscore the biological complexity of depression and may reduce stigma by demonstrating clear physiological changes beyond mood symptoms. “Not all depression is the same,” he added. “Each patient’s biology can differ, so identifying distinct bioenergetic profiles could lead to more precise and effective treatments.”
The study used a specialized brain imaging approach developed by Professors Xiao-Hong Zhu and Wei Chen to measure ATP production via 31P magnetic resonance spectroscopy imaging with magnetization transfer at 7 Tesla, and mitochondrial function tests on PBMCs. The work was led by Katie Cullen, MD, of the University of Minnesota.
Key Questions Answered:
Q: Why do I feel so tired if my cells are “overworking”?
A: Think of cells like an engine idling at high RPM. Even at rest they consume fuel and incur damage. When you try to meet additional demands—mental tasks or stress—there’s little reserve left, so performance and stamina drop, producing the deep fatigue associated with depression.
Q: Does this mean depression is a “mitochondrial disease”?
A: The findings support a view that mitochondrial dysfunction contributes to some symptoms of depression. The study shows reduced capacity of mitochondria to meet increased energy needs, which forms a biological basis for fatigue, low motivation, and slowed thinking, but it does not claim all aspects of depression are solely mitochondrial.
Q: Can a blood test diagnose depression now?
A: These results move the field closer to an objective blood-based marker by showing similar ATP patterns in brain and blood. More research and validation are needed before such a test could be used clinically.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was added by staff.
About this depression and neuroscience research news
Author: Pam Frost
Source: University of Queensland
Contact: Pam Frost – University of Queensland
Image: Image credit: Neuroscience News
Original Research: Open access. “ATP bioenergetics and fatigue in young adults with and without major depression” by Kathryn R. Cullen, Susannah J. Tye, Bonnie Klimes-Dougan, Hannes M. Wiesner, Roger B. Varela, Brooke Morath, Lin Zhang, Wei Chen & Xiao-Hong Zhu. Translational Psychiatry. DOI: 10.1038/s41398-026-03904-y
Abstract
ATP bioenergetics and fatigue in young adults with and without major depression
Fatigue is a pervasive and difficult-to-treat symptom of major depressive disorder (MDD) and contributes substantially to disability. Understanding the biological drivers of fatigue at early stages of illness is critical to preventing long-term negative outcomes.
This study measured bioenergetic markers—focusing on ATP concentration and ATP production rate—in the visual cortex and in peripheral blood mononuclear cells (PBMCs) of young adults with MDD compared with healthy controls. Brain ATP was measured using 31P magnetic resonance spectroscopy imaging with magnetization transfer at 7 Tesla. PBMC ATP was assessed at rest and after graded mitochondrial challenge.
From the available data (imaging usable for 18 participants; PBMCs for 24), the MDD group showed higher ATP production rates in the visual cortex and higher ATP concentrations in PBMCs at rest, both of which correlated with self-reported fatigue severity. After mitochondrial uncoupling, PBMCs from the MDD group had a lower capacity to increase ATP production than controls. These findings reveal a consistent ATP biosignature of fatigue visible in both brain and blood, suggesting an early compensatory mechanism in MDD that may ultimately limit cellular energy reserve.