Researchers identify a previously unknown mitochondrial disease in identical twins

Researchers identify a previously unknown mitochondrial disease in identical twins

Researchers led by researchers at Massachusetts General Hospital (MGH) and Children's Hospital Philadelphia (CHOP) have identified a previously unreported mitochondrial disease in a set of identical twins.

Diseases that affect mitochondria - specialized compartments within cells that contain their own DNA and convert the food we eat into energy needed to sustain life - typically impair mitochondrial function, but in these two patients the mitochondria were hyperactive.

As reported in the New England Journal of Medicine, their body weight remained very low even though the siblings consumed far more calories than necessary.

This is a highly unusual mitochondrial phenotype. There are more than 300 rare genetic mitochondrial diseases, and almost all are associated with mitochondrial disruption.”

Vamsi K. Mootha, MD, senior author, professor of systems biology and medicine at MGH

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Genome sequencing revealed a mutation in an enzyme called mitochondrial ATP synthase, which is needed by cells to generate the energy storage molecule ATP.

Experiments showed that this mutation creates "leaky" mitochondria that consume energy - a process called mitochondrial uncoupling.

“We propose a new name – mitochondrial uncoupling syndrome – which is characterized by hypermetabolism and uncoupled mitochondria,” says Mootha. “These cases are very important for the field of rare disease genetics, mitochondrial biology and metabolism.”

The authors note that additional studies on mitochondrial uncoupling syndromes could provide insights into differences in energy metabolism in the general population.

“These twins represent the first disruption of mitochondrial uncoupling where we have been able to find the genetic cause,” said Rebecca D. Ganetzky, MD, attending physician in the Mitochondrial Medicine Program at CHOP and co-author of the study.

“By discovering that pathogenic variants in ATP synthase itself can cause mitochondrial uncoupling, these twins may be the first identified patients in an entire class of mitochondrial coupling disorders.”

Additional co-authors include Andrew L. Markhard, BA, Irene Yee, BS, Sheila Clever, MSc, Alan Cahill, PhD, Hardik Shah, MS, Zenon Grabarek, PhD, and Tsz-Leung To, PhD.

This work was supported by the National Institutes of Health and others.

Source:

Massachusetts General Hospital

Reference:

Ganetzky, RD, et al. (2022) Innate hypermetabolism and uncoupled oxidative phosphorylation. New England Journal of Medicine. doi.org/10.1056/NEJMoa2202949.

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