期刊
JOURNAL OF INHERITED METABOLIC DISEASE
卷 44, 期 2, 页码 367-375出版社
WILEY
DOI: 10.1002/jimd.12345
关键词
ATP; bioenergetics; complex I; disulfide; electron transport chain; Leigh syndrome; metabolic disease; mitochondrial dysfunction; persulfide
资金
- United Mitochondrial Disease Foundation
- Brian Ridge Scholarship
- MRC [MR/S002626/1, MC_PC_16072] Funding Source: UKRI
The study demonstrates that selective targeting of mitochondria with H2S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders. It provides evidence that using AP39 could restore mitochondrial function in certain PMD models where mitochondrial dysfunction is the cause of the disease pathology.
Primary mitochondrial diseases (PMD) are inherited diseases that cause dysfunctional mitochondrial oxidative phosphorylation, leading to diverse multisystem diseases and substantially impaired quality of life. PMD treatment currently comprises symptom management, with an unmet need for therapies targeting the causative mitochondrial defects. Molecules which selective target mitochondria have been proposed as potential treatment options in PMD but have met with limited success. We have previously shown in animal models that mitochondrial dysfunction caused by the disease process could be prevented and/or reversed by selective targeting of the gasotransmitter hydrogen sulfide (H2S) to mitochondria using a novel compound, AP39. Therefore, in this study we investigated whether AP39 could also restore mitochondrial function in PMD models where mitochondrial dysfunction was the cause of the disease pathology using C. elegans. We characterised several PMD mutant C. elegans strains for reduced survival, movement and impaired cellular bioenergetics and treated each with AP39. In animals with widespread electron transport chain deficiency (gfm-1[ok3372]), AP39 (100 nM) restored ATP levels, but had no effect on survival or movement. However, in a complex I mutant (nuo-4[ok2533]), a Leigh syndrome orthologue, AP39 significantly reversed the decline in ATP levels, preserved mitochondrial membrane potential and increased movement and survival. For the first time, this study provides proof-of-principle evidence suggesting that selective targeting of mitochondria with H2S could represent a novel drug discovery approach to delay, prevent and possibly reverse mitochondrial decline in PMD and related disorders.
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