Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism
Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B. Bloch, Takaaki Akaike, Fumito Ichinose
Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B. Bloch, Takaaki Akaike, Fumito Ichinose
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Research Article Metabolism

Exclusion of sulfide:quinone oxidoreductase from mitochondria causes Leigh-like disease in mice by impairing sulfide metabolism

Abstract

Leigh syndrome is the most common inherited mitochondrial disease in children and is often fatal within the first few years of life. In 2020, mutations in the gene encoding sulfide:quinone oxidoreductase (SQOR), a mitochondrial protein, were identified as a cause of Leigh syndrome. Here, 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 hydrogen sulfide (H2S) levels. Because H2S is produced by both gut microbiota and host tissue, we tested whether metronidazole (a broad-spectrum antibiotic) or a sulfur-restricted diet rescues SqorΔN/ΔN mice from developing Leigh syndrome. Daily treatment with metronidazole alleviated increased H2S levels, normalized complex IV activity and blood lactate levels, and prolonged the survival of SqorΔN/ΔN mice. Similarly, a sulfur-restricted diet normalized blood lactate levels and inhibited the development of Leigh syndrome. Taken together, these observations suggest that mitochondrial SQOR is essential to prevent systemic accumulation of H2S. Metronidazole administration and a sulfur-restricted diet may be therapeutic approaches to treatment of patients with Leigh syndrome caused by mutations in SQOR.

Authors

Eiki Kanemaru, Kakeru Shimoda, Eizo Marutani, Masanobu Morita, Maria Miranda, Yusuke Miyazaki, Claire Sinow, Rohit Sharma, Fangcong Dong, Donald B. Bloch, Takaaki Akaike, Fumito Ichinose

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Figure 2

SqorΔN/ΔN mice had decreased complex IV activity, increased systemic H2S levels, and an impaired metabolic status.

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SqorΔN/ΔN mice had decreased complex IV activity, increased systemic H2S...
(A) Histochemical staining was used to measure cytochrome c oxidase (COX) activity in SqorΔN/ΔN and control mice. Control mouse brain, liver, and muscle sections are stained dark brown; the same tissues from SqorΔN/ΔN mice are light brown, indicating decreased complex IV activity. Scale bars: 100 μm. (B) Complex IV activity in isolated mitochondria of the brain, liver, and muscle. The mean values of complex IV activity in control mice were set to 100%. Comparisons were made using unpaired 2-tailed t test. n = 5–6 mice for each group. Data are presented as means with SD. (C) Sulfide levels in plasma, brain, liver, and muscle were measured using HSip-1. The sulfide levels in SqorΔN/ΔN mice were compared with those in control mice (the sulfide level for control mice was set to 1). Data were analyzed using Mann-Whitney test for plasma, and unpaired 2-tailed t test for brain, liver, and muscle. n = 5–8 mice for each group. Data are presented as medians with interquartile range for plasma, and as means with SD for brain, liver, and muscle. (D) Compared with control mice, the blood lactate levels in SqorΔN/ΔN mice were higher at postnatal ages 30, 40, and 50 days. Comparisons between SqorΔN/ΔN and control mice at postnatal ages 30, 40, and 50 days were made using unpaired 2-tailed t test. Mixed-effects analysis with Dunnett’s multiple-comparison test was performed to compare the blood lactate levels at postnatal ages 30, 40, and 50 days in SqorΔN/ΔN mice. n = 4–5 mice for each group. Data are presented as means with SD.