In Reply We thank Kozicz et al for their comments. There seems little discrepancy between our hypothesis that mitochondrial dysfunction is central to the etiology of neuropsychiatric disorders and their proposal that suboptimal mitochondrial function predisposes to neuropsychiatric disorders. Experiments to identify 1 or a few nuclear DNA (nDNA) gene defects that cause neuropsychiatric disorders have failed. For example, the search for the nDNA genetic “cause” of autism spectrum disorder has revealed numerous copy number variants and loss of function mutations, but each accounts for only a tiny fraction of autism spectrum disorder cases. By contrast, mitochondrial DNA (mtDNA) haplogroup lineages¹ and heteroplasmic (mixed mutant and normal) mtDNA variants² are present in a high proportion of autism spectrum disorder cases. These mtDNA variants are not sufficient in themselves to “cause” autism spectrum disorder. Rather, they are risk factors that must interact with other genetic or environmental factors to reduce bioenergetics sufficiently to impair the development and/or function of neuronal circuits.

在答复中，我们感谢Kozicz等人的评论。线粒体功能障碍是神经精神疾病病因的核心假设与他们关于线粒体功能欠佳易患神经精神疾病的建议之间似乎没有差异。鉴定导致神经精神疾病的1个或几个核DNA（nDNA）基因缺陷的实验失败了。例如，对自闭症谱系障碍的nDNA遗传“原因”的搜索揭示了许多拷贝数变异和功能突变，但每种仅占自闭症谱系障碍病例的一小部分。相比之下，线粒体DNA（mtDNA）单倍体谱系¹和异质（混合的突变体和正常）mtDNA变体²自闭症谱系障碍病例的比例很高。这些mtDNA变体本身不足以“引起”自闭症谱系障碍。相反，它们是必须与其他遗传或环境因素相互作用以充分减少生物能从而损害神经元回路的发育和/或功能的危险因素。