Mitochondrial Dysfunction and White Matter Injury

摘要 脑白质损伤(WMI)是儿童脑性瘫痪(CP)最常见的原因。最近， WMI的病理模式已从坏死性脑损伤转变为孤立或弥漫性髓鞘形成 肾小球系膜细胞成熟性缺陷所致的衰竭。而针对OL和其他组织的机制 WMI中的细胞退变已被广泛研究，其成熟失败的机制有 很神秘。我们假设，OLS的成熟性衰竭继发于其线粒体 功能障碍，为OL分化提供充足的能量供应。这场生物能量学危机并不致命 由多次短暂的低氧血症-复氧引起，这种事件在 早产儿。为了验证这一假设，我们提供了一种新的WM髓鞘形成失败的小鼠模型 早产儿的生理变化(全身氧合、心跳和呼吸频率) 间歇性低氧事件在新生小鼠中几乎重现。这个模型复制了感应器。 缺陷与人类的WMI表型一致。目标1将确定在此模型中，OL是否成熟 失效是髓鞘形成障碍的主要细胞学机制。目标2决定了 支持OL成熟和脑髓鞘形成的线粒体功能障碍。我们提议，在此期间 缺氧发作时，线粒体膜被瞬时通透性。这会短暂地阻止ATP 产生，因为质子动力随着线粒体膜的通透性而丧失。考虑到 早产儿经历50-200(！)在出生后的几周里，每天都会发生短暂的低氧事件， 支持足够的WM发展的生物能量学赤字代表了可以想象的机械论假说。 目的3确定线粒体膜瞬时通透性的抑制是否在 间歇性低氧可减轻WMI的严重程度。利用亲环素D KO小鼠，我们将确定一种致病因子 线粒体通透性在黄体细胞成熟的生物能量学危机中的作用。如果这个理论中的主要假设 如果提议得到确认，那么线粒体不能支持正常发育将被称为小说 WMI的机制。这确定了预防/治疗WMI的新的治疗目标：(1)限制 缺氧事件中线粒体膜通透性的研究。

SUMMARY White matter injury (WMI) is the most common cause of cerebral palsy (CP) in children. Recently, a pathological pattern of WMI have shifted from necrotic brain damage to isolated or diffuse myelination failure associated with maturational defect of olygodendrocytes (OLs). While mechanisms for OLs, and other cells degeneration in WMI have been extensively studied, the mechanisms of OLs maturational failure are cryptic. We hypothesized, that maturational failure of OLs occurs secondary to their mitochondrial dysfunction to provide adequate energy supply for OLs differentiation. This bioenergetics crisis is not lethal and caused by multiple, brief episodes of hypoxemia-reoxygenation, the event very commonly seen in premature infants. To test this hypothesis we offer a novel mouse model of WM myelination failure in which physiological changes (systemic oxygenation, heart and respiratory rates) seen in premature infants during intermittent hypoxic events were closely reproduced in neonatal mice. This model reproduces sensorimotor deficit consistent with WMI phenotype in humans. Aim 1 will determine if in this model, OLs maturational failure is the main cellular mechanism of myelination deficit. Aim 2 determines the mechanism for mitochondrial dysfunction to support OLs maturation and cerebral myelination. We propose, that during hypoxic episodes mitochondrial membrane is transiently permeabilized. This transiently arrests ATP production, as the proton motive force is lost with permeabilization of mitochondrial membrane. Given that premature infants experience 50 - 200 (!) brief hypoxemic events a day, for several postnatal weeks, bioenergetics deficit to support adequate WM development represents conceivable mechanistic hypothesis. Aim 3 determines whether an inhibition of transient permeabilization of mitochondrial membrane during intermittent hypoxia attenuates severity of WMI. Using cyclophilin D KO mice we will determine a pathogenic role for mitochondrial permeabilization in bioenergetics crisis of OLs maturation. If the main hypothesis in this proposal is confirmed, then mitochondrial failure to support proper development will be claimed as the novel mechanism for WMI. This identifies novel therapeutic goals in prevention/treatment of WMI: (1) limit mitochondrial membrane permeabilization during hypoxic event.