Mitochondrial disease makes the body burn more fuel to do less — in a small human study

Edited by Samael A. Tejada, Founder & Editor-in-Chief

The intuitive story says broken power plants should mean a body running on less. Measured carefully, in a metabolic lab and then in free living, the body with mitochondrial disease is doing something stranger: paying more for rest, and buying the difference back by moving less.

What exactly did the researchers measure?

Shaulson and colleagues compared 10 adults with mitochondrial disease against 10 healthy adults. Under controlled laboratory conditions, the mitochondrial-disease group expended approximately 195 additional calories per day despite moving less, with the elevation visible during sleep — a hypermetabolic pattern the authors call context-specific. For real-world measurement, Seth Creasy and Edward Melanson at the CU Anschutz Health and Wellness Center performed free-living energy-expenditure analyses using doubly labeled water, the gold-standard method for measuring calories burned during normal daily routines. That second measurement is what makes the study interesting: the lab difference did not show up as higher total daily expenditure at home.

Why did daily life look different from the lab?

Because the mitochondrial-disease group moved far less: approximately 39 percent less physically active. The authors' interpretation is that reduced activity compensates for higher underlying energy costs — the body's budget balances, but it balances by shrinking the activity line rather than the resting line. That reframes a familiar clinical observation. Fatigue and exercise intolerance in mitochondrial disease are usually described as consequences of weak energy production; this study suggests they may also be, in part, an economy measure by a system whose baseline running costs are elevated. It also means a simple 'calories burned' number, without the activity context, would have hidden the entire finding.

What is GDF15 doing in this story?

GDF15 is a stress-signaling protein this site's testing coverage meets often: mitochondria under strain release it, and blood levels are used as a biomarker pointing toward mitochondrial disease. Here, GDF15 levels were nearly five times higher in the mitochondrial-disease group and were associated with greater fatigue, higher energy demands and reduced physical activity — tying the molecular stress signal to the whole-body energy pattern in the same people. The boundaries matter: this is a 10-versus-10 comparison, the associations are cross-sectional, and nothing here shows that lowering GDF15 or changing expenditure would help anyone. What the study establishes is a measurable human physiology — elevated resting costs, compensatory inactivity, and a stress marker that tracks both — that larger studies can now test properly.

Where the evidence stands

• Established: GDF15 is a mitochondrial stress-signaling protein whose blood levels rise in mitochondrial disease; doubly labeled water is the gold-standard method for measuring free-living energy expenditure; and fatigue and exercise intolerance are core features of mitochondrial disease.
• Preliminary: In 10 adults with mitochondrial disease vs 10 healthy adults (Cell Press Blue, 2026; DOI 10.1016/j.cpblue.2026.100129), laboratory energy expenditure was ~195 kcal/day higher in the disease group (including during sleep), free-living total expenditure was similar because the disease group was ~39% less active, and GDF15 was nearly 5x higher and associated with fatigue, energy demands and inactivity.
• Absent: Replication in larger cohorts, longitudinal data, any causal test of the activity-compensation interpretation, and any intervention.