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；严重抑郁障碍，MDD)在全球范围内造成终身残疾的高比例，寿命缩短，以及毁灭性的个人影响。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从基因突变中遗传，并可影响包括大脑在内的多个靶器官。我们认为，发生情绪障碍的部分风险是涉及线粒体DNA(MtDNA)的遗传变异。我们复制了我们最初的发现，与对照组相比，情绪障碍患者常见的4977个碱基对的线粒体DNA大片段缺失增加。值得注意的是，线粒体DNA的大量缺失更多地出现在代谢率较高的组织中，如大脑和肌肉，并以年龄相关的方式积累。我们相信，对大片段缺失和可能转化为蛋白质的全谱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。在这项建议中，我们假设大量体细胞mtDNA缺失在大脑中积累，在情绪障碍中达到高水平，导致线粒体功能异常。我们提出了三个具体目标，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，从中提取与认知、情感调节和情绪障碍相关的14个脑区。2)构建人脑mtDNA和cDNA大片段缺失序列谱。3)确定大片段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，现在准备筛选可能导致精神疾病中线粒体功能障碍的mtDNA全谱缺失。与已知的常见mtDNA缺失相比，这些新的缺失发生在大脑样本中的水平甚至更高。目前，还没有关于蛋白质翻译或这些大片段缺失对人脑功能影响的报道。为了合作研究，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的新治疗方法，并减少体细胞缺失的积累，从而改进情绪障碍的治疗。

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.