Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

描述（由申请人提供）：线粒体是通过氧化磷酸化过程为脑细胞提供大部分能量的细胞器。线粒体异常和氧化磷酸化缺陷在精神分裂症（SZ）和双相情感障碍（BD）患者中有报道。根据转录组学、蛋白质组学和代谢组学研究、家族遗传研究、体内神经影像学研究和线粒体DNA （mtDNA）序列变异的证据，该基金的主要假设是线粒体功能障碍是SZ和BD的危险因素之一。在SZ和BD患者中已经报道了一些轻度有害的mtDNA突变。研究人员发现，相对于年龄匹配的对照组，双相障碍受试者的大脑背外侧前额叶皮层（DLPFC）中mtDNA的大部分缺失增加。与对照组相比，SZ患者DLPFC中整个mtDNA基因组中同义碱基对的替换量增加，并且SZ患者的10个mtDNA转录本的表达量显著降低。SZ中mtDNA转录本表达的减少可能与对照区或编码区mtDNA取代的增加有关。SZ中碱基对替换增加的原因可能是遗传或脑内累积的替换。这项拨款的两个目的是研究大脑中mtDNA的替代，并比较同一受试者生殖系组织中的替代率。本项目拟检测SZ和BD患者大脑中mtDNA的常见缺失、拷贝数和转录物丰度，并与对照组进行比较。脑内新的mtDNA取代和缺失的积累可能是BD和SZ的危险因素，对确定未来慢性情绪和精神障碍的治疗靶点具有重要的潜在意义。这项研究填补了一个空白，因为目前还没有对患有精神疾病的同一受试者进行整个线粒体基因组和转录组的综合脑研究。脑线粒体基因组和转录组数据的全面整合可以显示一个或两个系统的中度功能障碍是否导致疾病阈值。关注线粒体作为功能性脑缺陷的靶细胞器，可能会导致改善线粒体健康和脑功能的综合治疗的改进。精神分裂症和双相情感障碍的病因尚未被发现。这笔拨款提议分析包含在脑细胞中的线粒体DNA，它可能包含异常的结构和序列。大脑中线粒体序列的改变可能会增加患严重精神障碍的风险。通过了解线粒体DNA缺陷在大脑中的积累，将推动线粒体医学的早期诊断和治疗脑相关疾病。

DESCRIPTION (provided by applicant): Mitochondria are organelles that provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in individuals with schizophrenia (SZ) and bipolar disorder (BD). The overarching hypothesis for this grant is that mitochondrial dysfunction is one of the risk factors for SZ and BD based upon evidence of mitochondrial dysfunction in transcriptomic, proteomic, and metabolomic studies, genetic studies of families, in vivo neuroimaging studies, and mitochondrial DNA (mtDNA) sequence variations. Several mildly deleterious mutations in mtDNA have been reported in SZ and BD patients. The investigators found deletion of a large portion of mtDNA was increased in the brain, dorsolateral prefrontal cortex (DLPFC), of BD subjects relative to age-matched controls. The substitution of synonymous base pairs in the entire mtDNA genome was elevated in DLPFC of individuals with SZ compared to controls and subjects with SZ had a significantly decreased expression of 10 mtDNA transcripts. The decreased expression of mtDNA transcripts in SZ might be related to increased mtDNA substitution in the control or coding regions which will be tested. The causes for increased base pair substitutions in SZ might be inherited or accumulated substitutions in brain. Two of the aims for this grant are to study mtDNA substitutions in brain and to compare the substitution rate in the same subjects9 germ line tissue. This grant proposes to examine mtDNA common deletion, copy number, and transcript abundances in brain from individuals with SZ and BD and compare to controls. The accumulation of novel mtDNA substitutions and deletions in brain might be a risk factor for BD and SZ, and has a great potential significance in determining future targets for therapy of chronic mood and psychotic disorders. This study fills a void as there has not been an integrative brain study of the entire mitochondrial genome and transcriptome conducted in the same subjects with psychiatric disorders. A comprehensive integration of data from the genome and transcriptome of brain mitochondria can show whether moderate dysfunction in one or both systems leads to disease threshold. Focusing on the mitochondria, as a target organelle of functional brain deficits, may lead to improvements in integrative treatments that improve mitochondrial health and brain function. PUBLIC HEALTH RELEVANCE: Project Narrative/Relevance The causes of schizophrenia and bipolar disorder have not been discovered. This grant proposes to analyze mitochondrial DNA, contained in brain cells, which might harbor abnormal structure and sequence. Alterations in mitochondrial sequence during the lifespan in brain might contribute to risk of developing a serious mental disorder. By understanding the accumulation of mitochondrial DNA defects in brain, it will advance mitochondrial medicine for earlier diagnosis and treatment of brain related disorders.