Mitochondrial Deletions in Mood Disorders

描述（由申请人提供）：心境障碍中的线粒体缺失心境障碍（双相情感障碍，BD;重性抑郁症，MDD）在世界范围内占终身残疾的很高比例，寿命缩短，和毁灭性的个人影响.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以从基因突变中遗传，并且可以影响多个靶器官，包括大脑。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。我们重复了我们最初的发现，即与对照组相比，情绪障碍患者的mtDNA中有4，977个碱基对的大的常见体细胞缺失。值得注意的是，这些mtDNA的大缺失更频繁地出现在具有高代谢率的组织中，如大脑和肌肉，并以年龄依赖性的方式积累。我们相信，对全谱大缺失和可能翻译成蛋白质的研究将提供大量证据支持线粒体功能障碍在心境障碍中的作用。在这个建议中，我们假设，大的体细胞mtDNA缺失在大脑中积累到高水平的情绪障碍，导致线粒体功能异常。我们提出了三个具体目标，重点是MDD和BD中大缺失的积累。1)从人脑中收集新鲜的线粒体（10个MDD，10个BD和10个对照），我们将从其中取样14个涉及情绪障碍中的认知，情感调节和快感缺失的脑区。2)生成人脑中mtDNA和cDNA的大缺失序列谱。3)确定大缺失序列对蛋白质和线粒体功能的影响。我们已经在死后人脑中发现了新的大的体细胞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缺失的全谱。与已知的常见mtDNA缺失相比，这些新的缺失在大脑样本中的水平甚至更高。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，我们将在NCBI上共享所有mtDNA缺失序列。这些结果可能导致新的治疗方法，靶向线粒体功能缺陷，减少体细胞缺失的积累，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.