Anaplerotic Therapy for Mitochondrial Complex I Deficiency

摘要 表现为脑病的线粒体疾病的发生率为1/5000活产，并且通常是 在生命的最初几年就致命。线粒体疾病是呼吸链疾病，其中线粒体 不再有效地生产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过程，例如Leigh综合征， 被很好地描述，精确的生化改变，有助于神经病理学，超越ATP缺陷， 更少被理解。 我们先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，以产生不可逆的修饰，2-琥珀半胱氨酸（2SC）。我们已经描述了增加的2SC 在几种模型中，包括线粒体复合物I缺陷的Ndufs 4敲除小鼠模型。 该提案中显示的初步数据将α-酮戊二酸的一种组分的琥珀酸化 脱氢酶（α-KGDH）复合物的功能缺陷。这将导致减少 琥珀酰辅酶A的产生，并损害底物水平磷酸化，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景观。此外，我们注意到， 酸中毒结合Ndufs 4生物能量缺陷也会影响受影响区域的活化小胶质细胞 通过抑制一种抗炎代谢物的产生，我们假设这会导致 未解决的炎症可能进一步加剧神经元细胞死亡。我们的新数据表明，柠檬酸 酸循环功能障碍在介导受影响最大的区域内的生化损伤中起关键作用。 病理在这份提案中，我们概述了几种有针对性的回补疗法，以及一种改进的递送方法， 可以改善这些生化缺陷重要的是，由于这些化合物无毒， 燃料，它们可以与现有的维生素/抗氧化剂结合，以支持神经元的健康。

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.