Mitochondrial Deletions in Mood Disorders

描述（由申请人提供）：情绪障碍中的线粒体缺失情绪障碍（双相情感障碍，BD；重度抑郁症，MDD）在全球范围内占终生残疾的高比例，缩短寿命，并对个人造成毁灭性的影响。情绪障碍的病理生理学，涉及能量代谢和线粒体功能的主要异常。线粒体功能障碍和疾病可以从基因突变遗传，并可以影响多个目标器官，包括大脑。我们认为，发生情绪障碍的部分风险是与线粒体DNA （mtDNA）有关的遗传变异。我们已经重复了我们最初的发现，即与对照组相比，情绪障碍患者中4977个mtDNA碱基对的大量常见体细胞缺失增加。值得注意的是，这些mtDNA的大缺失更频繁地出现在高代谢率的组织中，如大脑和肌肉，并以年龄依赖的方式积累。我们相信，对大缺失的全谱研究和可能转化为蛋白质的研究将提供大量证据，支持线粒体功能障碍在情绪障碍中的作用。在这一提议中，我们假设在心境障碍中，大量体细胞mtDNA缺失在大脑中积累到高水平，导致线粒体功能异常。我们提出了三个特定目标，重点关注MDD和BD中大量缺失的积累：1)从人脑（10个MDD， 10个BD和10个对照）中收集新鲜线粒体，从中我们将取样涉及认知，情感调节和心境障碍快感缺乏的14个大脑区域。2)生成人脑mtDNA和cDNA大缺失序列谱。3)确定大缺失序列对蛋白质和线粒体功能的影响。我们已经在死后的人类大脑中发现了新的大型体细胞mtDNA缺失，现在我们准备筛选可能导致精神疾病线粒体功能障碍的mtDNA缺失的全谱。与已知的常见mtDNA缺失相比，这些新的缺失在脑样本中出现的水平甚至更高。目前，还没有关于这些大缺失在人脑中的蛋白质翻译或功能影响的报道。为了合作研究的利益，我们将在NCBI共享所有mtDNA缺失序列。这些结果可能导致针对线粒体功能缺陷和减少体细胞缺失积累的新疗法，从而改善情绪障碍的治疗。

DESCRIPTION (provided by applicant): Mitochondrial Deletions in Mood Disorders Mood disorders (bipolar disorder, BD; major depressive disorder, MDD) account for a high percentage of life- time disability on a world-wide basis, shortened life span, and devastating personal impacts. The pathophysiology of mood disorders, implicates major abnormalities in energy metabolism and mitochondrial function. Mitochondrial dysfunction and disease can be inherited from genetic mutation and can affect multiple target organs, including the brain. We believe that part of the risk for developing mood disorders is genetic variation involving mitochondria DNA (mtDNA). We have replicated our initial findings that a large common somatic deletion of 4,977 base pairs of mtDNA is increased in mood disorders compared to controls. It is important to note that these large deletions of mtDNA appear more frequently in tissues with high metabolic rates, such as brain and muscle and accumulate in an age dependent manner. We believe the study of the full spectrum of large deletions and possible translation into protein will provide substantial evidence supporting the role of mitochondrial dysfunction in mood disorders. In this proposal we hypothesize that large somatic mtDNA deletions accumulate in brain to high levels in mood disorders leading to abnormalities in mitochondrial function. We propose three Specific Aims focusing on the accumulation of large deletions in MDD and BD. 1) Collect fresh mitochondria from human brain (10 MDD, 10 BD, and 10 controls) from which we will sample fourteen brain regions implicated in cognition, affective regulation, and anhedonia in mood disorders. 2) Generate a spectrum of large deletion sequences in mtDNA and cDNA in human brain. 3) Determine the impact of large deletion sequences on proteins and on mitochondria function. We have already discovered novel large somatic mtDNA deletions in postmortem human brains, and are now ready to screen the full spectrum of mtDNA deletions that might cause mitochondrial dysfunction in psychiatric disorders. These novel deletions occur in brain samples at even higher levels compared to the known common deletion of mtDNA. Currently, there are no reports of either protein translation or functional effects of these large deletions i human brain. In the interest of collaborative research, we will share all mtDNA deletion sequences at NCBI. These results could lead to novel treatments that target mitochondrial functional deficits and reduce the accumulation of somatic deletions, thereby improving therapy of mood disorders.