The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model
The mitochondria-targeted hydrogen sulfide donor AP39 improves health and mitochondrial function in a C. elegans primary mitochondrial disease model
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DOI：
10.1002/jimd.12345
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发表时间：
2021-01-20
影响因子：
4.2
通讯作者：
Whiteman, Matthew
中科院分区：
文献类型：
--
作者：
Fox, Bridget C.;Slade, Luke;Whiteman, Matthew
原发性线粒体疾病（PMD）是一种遗传性疾病，可引起线粒体氧化磷酸化功能障碍，导致多种多系统疾病和生活质量严重受损。PMD治疗目前包括症状管理，对靶向致病性线粒体缺陷的疗法的需求未得到满足。选择性靶向线粒体的分子已被提出作为PMD的潜在治疗选择，但成功有限。我们先前已经在动物模型中表明，由疾病过程引起的线粒体功能障碍可以通过使用新型化合物AP 39选择性靶向“气体传递剂”硫化氢（H2S）到线粒体来预防和/或逆转。因此，在本研究中，我们使用C.优雅我们鉴定了几种PMD突变体C。elegans菌株的存活率、运动和细胞生物能量学受损，并分别用AP 39处理。在广泛性电子传递链缺陷（gfm-1[ok 3372]）的动物中，AP 39（100 nM）恢复了ATP水平，但对存活或运动没有影响。然而，在复合物I突变体（nuo-4[ok 2533]）（Leigh综合征直系同源物）中，AP 39显著逆转了ATP水平的下降，保留了线粒体膜电位，并增加了运动和存活。这项研究首次提供了原理性证据，表明用H2S选择性靶向线粒体可能代表一种新的药物发现方法，可以延迟，预防并可能逆转PMD和相关疾病中的线粒体下降。
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.