恢复细胞能量信号可以提供治疗人类线粒体疾病的承诺

源于小小的发电厂，使我们的细胞发生故障，线粒体疾病是众所周知的复杂多变，几乎没有有效的治疗方法。现在，新发现的微小蠕虫病毒可能会对儿童和成人有巨大的潜力与线粒体疾病。利用现有的人类药物改善代谢和恢复缩短寿命在这些实验室动物，科学家们有可能的创新疗法的人体临床试验，设置阶段为线粒体疾病。

线粒体是目前高达几百份，几乎在每一个细胞，但是当他们不工作，他们损害了许多系统在人体正常的能量流通过短路。虽然原发性线粒体疾病是个别罕见的，数以百计的存在，至少在5000个人的集体影响。异常线粒体功能在2型糖尿病、癫痫、阿尔茨海默病、甚至人类衰老等共同的情况下也起着重要作用。

“这项工作进行识别线粒体疾病有效治疗的强有力的承诺，”研究的领导者Marni J。法尔克，MD说，主任和主治医生在线粒体遗传病门诊在费城儿童医院（CHOP）。“我们在这项研究中使用的药物，提高细胞信号的方式，可以直接受益的患者。因为所有的药物都是目前规定的其他疾病，他们已经可以在临床试验中的患者与线粒体疾病的测试。

法尔克和他的同事在杂志上发表了他们的研究，3月3日在杂志上线粒体。

关注呼吸链缺陷

这个current research focuses on the respiratory chain, a set of five enzyme complexes that together are a crucial site of energy production inside mitochondria。 In respiratory chain (RC) defects, common culprits in many mitochondrial disorders, cells fail to properly produce energy。 这个most common site of RC dysfunction is complex I, a group of proteins that normally generates a key metabolic product, nicotinamide adenine dinucleotide (NAD+)。

NAD+ normally regulates hundreds of other chemical reactions within the cell。 When genetic mutations disrupt complex I proteins and the metabolic conversion of NADH to NAD+, patients may suffer often-severe energy shortages in the heart, brain, eyes, muscles and many other parts of the body。

Green areas in a mutant worm show areas of biological stress from defective mitochondria。 In the current study, Falk and colleagues studied microscopic worms with mutations that disrupt their mitochondria and make them a useful laboratory model for investigating mitochondrial disease。 Using these nematodes, called 秀丽隐杆线虫, Falk’s research laboratory has done extensive studies to understand mitochondrial disease and potential therapies。

测试现有的药物作为潜在的治疗方法

这个researchers tested a series of drugs currently used to treat patients with diabetes or lipid disorders。 One drug, nicotinic acid, is a form of niacin (vitamin B3) that has been used for decades to treat patients who have high triglycerides in their blood。

这个C。 elegans worms had mutations that directly impaired their complex I function and shortened their lifespans。 Nicotinic acid restored the worms’ lifespans to that of normal animals。 It also restored the levels of NADH, enabling it to play its crucial role of initiating the transport of electrons in the RC that is necessary to produce cellular energy, as well as regulating many other cellular processes。

这个team showed that other available human drugs also improved key metabolite levels in C。 elegans。 “In contrast to research that aims to repair defective mitochondria, we are bypassing the damaged mitochondria and focusing instead on how cells respond to mitochondrial problems,” said Falk。 “We’re restoring the ratio of critical metabolic precursors and products that control signaling pathways, thereby improving overall cellular health in respiratory chain diseases。”

Mitochondrial diseases, she added, are highly complex, but her team’s series of nematode studies have revealed fundamental conserved processes that are disrupted in mitochondrial disease。 这个study team carefully deciphered many of the biological mechanisms at work, marked by changes in oxidant levels, genome expression patterns and other major physiological effects。 “Although some specific mechanistic details may differ, we’re looking at how the effects of different drugs may converge to promote an organism’s health and survival,” she said。

临床试验计划

Falk and colleagues are now planning a pilot clinical trial in children with complex I deficiencies to determine whether the effects seen in the animals will translate to meaningful clinical benefits in patients。 Ultimately, she expects the complexity of mitochondrial biology will dictate that effective treatments will require combination therapies specific to restoring signaling pathways that are commonly disrupted in major subtypes of mitochondrial disease。 “We’re enthusiastic that we have reached a major threshold on the path toward bringing important new therapies to a very challenging group of diseases,” she added。

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