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.

中文翻译：

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关于情绪障碍，线粒体 DNA 分析可以告诉我们什么？

几十年来，人们对双相情感障碍、抑郁症或其他精神疾病中的线粒体 DNA (mtDNA) 和编码线粒体蛋白的核基因的变异进行了研究，因为这些疾病患者的大脑中首次提出了线粒体功能障碍。候选基因关联研究最初的结果与线粒体功能障碍假说相符。然而，其中许多研究是在样本量适中 (N < 1000) 的情况下进行的，这可能会导致假阳性结果。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。一个悬而未决的关键问题是，情绪障碍与积累大量 mtDNA 突变和/或参与情绪调节的大脑区域中的体细胞 mtDNA 突变（缺失和点突变）之间是否存在关联。支持 mtDNA 突变在脑组织中对情绪障碍的重要性的两条有力证据来自对携带原发性 mtDNA 突变或由于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和动物模型研究。超过一半的线粒体疾病患者合并有情绪障碍，并且具有 mtDNA 突变的神经元特异性积累的小鼠表现出自发的抑郁样发作。在这次审查中，我们首先总结了 mtDNA 及其遗传学的当前知识，并基于帕金森病的一个例子讨论了 mtDNA 分析告诉我们关于神经精神疾病的什么。我们还讨论了超越 mtDNA 分析的挑战和未来方向，以了解“特发性”情绪障碍的病理生理学。