Mitochondrial Abnormalities in Schizophrenia and Bipolar Disorder

描述(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。据报道，精神分裂症(SZ)和双相情感障碍(BD)患者存在线粒体氧化磷酸化异常和缺陷。根据转录学、蛋白质组学和代谢组学研究、家族遗传研究、体内神经成像研究和线粒体DNA(MtDNA)序列变异中的线粒体功能障碍证据，这项赠款的主要假设是线粒体功能障碍是SZ和BD的风险因素之一。已有报道在SZ和BD患者中发现了几种轻度有害的mtDNA突变。研究人员发现，与年龄匹配的对照组相比，BD受试者大脑背外侧前额叶皮质(DLPFC)中很大一部分mtDNA的缺失增加。与对照组相比，SZ患者DLPFC中线粒体DNA全基因组同义碱基对的替换增加，而SZ患者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将要检测的控制区或编码区的mtDNA替代增加有关。SZ碱基对替换增加的原因可能是遗传或脑内累积的替换。这项资助的两个目的是研究大脑中线粒体DNA的替换，并比较相同受试者9生殖系组织中的替换率。这项资助计划检测SZ和BD患者大脑中线粒体DNA的共同缺失、拷贝数和转录丰度，并与对照组进行比较。新的mtDNA替换和缺失在脑内的积累可能是BD和SZ的危险因素，对确定未来治疗慢性情绪和精神障碍的靶点具有重要的潜在意义。这项研究填补了一项空白，因为还没有对同一精神障碍受试者进行完整的线粒体基因组和转录组的大脑研究。对来自大脑线粒体基因组和转录组的数据进行全面整合，可以表明一个系统或两个系统的中度功能障碍是否会导致疾病阈值。专注于线粒体，作为功能性大脑缺陷的靶细胞器，可能会导致综合治疗的改进，从而改善线粒体健康和大脑功能。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。这项拨款建议分析包含在脑细胞中的线粒体DNA，它可能含有异常的结构和序列。在大脑的一生中，线粒体序列的改变可能会导致严重的精神障碍。通过了解线粒体DNA缺陷在脑内的蓄积情况，将推动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.