Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Biol Psychiatry. 2018 May 1;83(9):731-738. doi: 10.1016/j.biopsych.2017.09.010. Epub 2017 Sep 21.
Variants in mitochondrial DNA (mtDNA) and nuclear genes encoding mitochondrial proteins in bipolar disorder, depression, or other psychiatric disorders have been studied for decades, since mitochondrial dysfunction was first suggested in the brains of patients with these diseases. Candidate gene association studies initially resulted in findings compatible with the mitochondrial dysfunction hypothesis. Many of those studies, however, were conducted with modest sample sizes (N < 1000), which could cause false positive findings. Furthermore, the DNA samples examined in these studies, including genome-wide association studies, were generally derived from peripheral tissues. One key unanswered question is whether there is an association between mood disorders and somatic mtDNA mutations (deletions and point mutations) in brain regions that accumulate a high amount of mtDNA mutations and/or are involved in the regulation of mood. Two lines of robust evidence supporting the importance of mtDNA mutations in brain tissues for mood disorders have come from clinical observation of mitochondrial disease patients who carry primary mtDNA mutations or accumulate secondary mtDNA mutations due to nuclear mutations and an animal model study. More than half of mitochondrial disease patients have comorbid mood disorders, and mice with neuron-specific accumulation of mtDNA mutations show spontaneous depression-like episodes. In this review, we first summarize the current knowledge of mtDNA and its genetics and discuss what mtDNA analysis tells us about neuropsychiatric disorders based on an example of Parkinson's disease. We also discuss challenges and future directions beyond mtDNA analysis toward an understanding of the pathophysiology of "idiopathic" mood disorders.
几十年来，人们一直在研究双相情感障碍、抑郁症或其他精神疾病中线粒体 DNA (mtDNA) 和编码线粒体蛋白的核基因的变异，因为最初在这些疾病患者的大脑中发现了线粒体功能障碍。候选基因关联研究最初得出的结果与线粒体功能障碍假说一致。然而，其中许多研究的样本量较小（N < 1000），这可能导致假阳性发现。此外，这些研究中检查的 DNA 样本，包括全基因组关联研究，通常来自外周组织。一个关键的未解决问题是，在大脑区域中是否存在情绪障碍与体细胞 mtDNA 突变（缺失和点突变）之间的关联，这些区域积累了大量的 mtDNA 突变，并且/或者参与了情绪的调节。有两条强有力的证据支持 mtDNA 突变在情绪障碍的脑组织中的重要性，这来自于对携带原发性 mtDNA 突变或因核突变而积累继发性 mtDNA 突变的线粒体疾病患者的临床观察，以及一项动物模型研究。超过一半的线粒体疾病患者有共患的情绪障碍，并且神经元特异性积累 mtDNA 突变的小鼠会出现自发性抑郁样发作。在这篇综述中，我们首先总结了 mtDNA 及其遗传学的现有知识，并基于帕金森病的一个例子讨论了 mtDNA 分析告诉我们的关于神经精神疾病的信息。我们还讨论了 mtDNA 分析之外理解“特发性”情绪障碍的病理生理学的挑战和未来方向。
