Fumito Ichinose, MD, PhD, a physician-investigator in the department of Anesthesia, Critical Care and Pain Medicine at Massachusetts General Hospital and William Thomas Green Morton Professor of Anaesthesia at Harvard Medical School, is corresponding author of a new study in the Journal of Clinical Investigation, Exclusion of Sulfide:Quinone Oxidoreductase From Mitochondria Causes Leighlike Disease in Mice by Impairing Sulfide Metabolism.

What Question Were You Investigating in this Study?

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal.

In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome.

We asked whether mutation of SQOR causes accumulation of sulfide and if so, would measures to reduce systemic sulfide load rescue mice with SQOR mutation?

What Were the Results?

We report that mice with a mutation in the gene encoding SQOR (SqorΔN/ΔN mice), which prevented SQOR from entering mitochondria, had clinical and pathological manifestations of Leigh syndrome.

SqorΔN/ΔN mice had increased blood lactate levels that were associated with markedly decreased complex IV activity and increased hydrogens sulfide levels.

Treatment with metronidazole, a broad spectrum antibiotics, or feeding a sulfur-restricted diet ameliorated the neurodegeneration and prolonged survival of SqorΔN/ΔN mice.

What are the Clinical Implications or Next Steps?

Hydrogen sulfide is produced from our cells and gut bacteria and used in mitochondria (“powerhouse” of the cells).

Some children are born with a defective enzyme that can't properly use hydrogen sulfide, leading to a serious brain condition called Leigh syndrome, which can be fatal.

Drugs or special diet that decrease hydrogen sulfide production in our body may alleviate the brain disease and save these children.

Paper Cited:

Kanemaru, E., Shimoda, K., Marutani, E., Morita, M., Miranda, M., Miyazaki, Y., Sinow, C., Sharma, R., Dong, F., Bloch, D. B., Akaike, T., & Ichinose, F. (2024). Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolismThe Journal of clinical investigation, e170994. Advance online publication. https://doi.org/10.1172/JCI170994