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已被报道在精神分裂症（SZ）和双相情感障碍（BD）的个人。这项资助的总体假设是，线粒体功能障碍是SZ和BD的风险因素之一，基于转录组学、蛋白质组学和代谢组学研究、家族遗传学研究、体内神经影像学研究和线粒体DNA（mtDNA）序列变异中线粒体功能障碍的证据。在SZ和BD患者中已经报道了几种轻微有害的mtDNA突变。研究人员发现，相对于年龄匹配的对照组，BD受试者的大脑背外侧前额叶皮层（DLPFC）中大部分mtDNA的缺失增加。与对照组相比，SZ个体的DLPFC中整个mtDNA基因组中同义碱基对的替换升高，SZ受试者的10个mtDNA转录本的表达显著降低。SZ中mtDNA转录本表达的降低可能与对照或编码区中mtDNA取代的增加有关。SZ碱基替换增加的原因可能是遗传或脑内累积的替换。该基金的两个目的是研究脑中mtDNA的替代，并比较相同受试者9生殖系组织中的替代率。这项资助计划研究SZ和BD患者脑中mtDNA常见缺失、拷贝数和转录本丰度，并与对照组进行比较。脑组织中新的mtDNA替换和缺失的积累可能是BD和SZ的危险因素，对确定慢性心境障碍和精神病性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，因为还没有一个完整的线粒体基因组和转录组的大脑研究在同一个主题与精神疾病。来自脑线粒体基因组和转录组的数据的全面整合可以显示一个或两个系统中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，可能会改善改善线粒体健康和脑功能的综合治疗。公共卫生相关性：项目叙述/相关性精神分裂症和双相情感障碍的原因尚未发现。这项资助计划用于分析脑细胞中可能含有异常结构和序列的线粒体DNA。在生命周期中，大脑中线粒体序列的改变可能会导致严重精神障碍的风险。通过了解线粒体DNA缺陷在脑中的积累，将促进线粒体医学对脑相关疾病的早期诊断和治疗。

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.