Anaplerotic Therapy for Mitochondrial Complex I Deficiency

摘要 表现为脑病的线粒体疾病以每5000名活产儿中有1名的比率发生，通常 在生命的最初几年是致命的。线粒体疾病是呼吸链疾病，其中线粒体 不再有效地运行以生产ATP，通常是由于一个或多个组件的问题 氧化磷酸化机制。这些脑病的临床病程，如利综合征， 都被描述得很好，除了三磷酸腺苷缺陷之外，导致神经病理的精确生化变化， 却鲜为人知。 我们之前已经描述了柠檬酸循环代谢产物富马酸与蛋白质半胱氨酸的反应。 残基产生不可逆转的修饰，2-琥珀酸半胱氨酸(2SC)。我们已经描述了增加的2SC 在几个模型中，包括线粒体复合体I缺乏的Ndufs4基因敲除小鼠模型。 该提案中显示的初步数据将α-酮戊二酸的一个组分的琥珀酸化 脱氢酶复合体(α-KGDH)对此酶复合体的功能缺陷。这导致减少了 琥珀酰辅酶A的产生，并损害底物水平的磷酸化，以产生急需的GTP。我们 假设α-KG在酸性条件下转化为2-羟基戊二酸，即乳酸酸中毒。 我们预测，这会影响受影响神经元的表观遗传格局。此外，我们注意到新陈代谢 酸中毒合并Ndufs4生物能量缺陷也影响了受影响区域激活的小胶质细胞 通过抑制一种抗炎代谢物的产生来影响大脑。我们假设这会导致 未解决的炎症，可能会进一步加剧神经细胞死亡。我们的新数据表明，柠檬酸 酸循环功能障碍在调节受影响最严重的区域的生化损害中起着关键作用 病理学。在这项提案中，我们概述了几种有针对性的止痛疗法，以及一种改进的给药方法， 这应该会改善这些生化缺陷中的一些。重要的是，因为这些化合物是无毒的 作为燃料，它们可以与现有的维生素/抗氧化剂结合起来，以支持神经元健康。

ABSTRACT Mitochondrial diseases manifesting as encephalopathies occur at a rate of 1 in 5000 live births and are often fatal in the first few years of life. Mitochondrial diseases are respiratory chain disorders in which the mitochondria are no longer operating efficiently to produce ATP, usually due to a problem with one or more components of the oxidative phosphorylation machinery. The clinical course of these encephalopathies, e.g. Leigh Syndrome, are well-described, the precise biochemical alterations that contribute to neuropathology, beyond the ATP defect, are less understood. We have previously described the reaction of the citric acid cycle metabolite fumarate with protein cysteine residues to generate an irreversible modification, 2-succinocysteine (2SC). We have described increased 2SC in several models, including the Ndufs4 knockout mouse model of mitochondrial Complex I deficiency. Preliminary data shown in this proposal links the succination of a component of the α-ketoglutarate dehydrogenase (α-KGDH) complex to the defective function of this enzyme complex. This results in decreased succinyl CoA production, and impaired substrate level phosphorylation to produce much needed GTP. We hypothesize that the α-KG is instead converted to 2-hydroxyglutarate under acidic conditions, i.e. lactic acidosis. We predict that this influences the epigenetic landscape in the affected neurons. Further, we note that metabolic acidosis combined with Ndufs4 bioenergetic defect also impacts the activated microglia in the affected regions of the brain, by suppressing production of an anti-inflammatory metabolite. We hypothesize that this leads to unresolved inflammation that may further exacerbate neuronal cell death. Our novel data suggests that citric acid cycle dysfunction plays a key role in mediating the biochemical damage within the regions most affected by pathology. In this proposal we outline several targeted anaplerotic therapies, and an improved delivery method, that should ameliorate some of these biochemical defects. Importantly, since these compounds are non-toxic fuels, they can be combined with existing vitamin/antioxidants to support neuronal health.