Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a pathogenic variant, variant allele frequency (VAF), must reach a threshold before a biochemical defect occurs, termed the biochemical threshold. Whether the often-cited biochemical threshold of >60% VAF is similar across mtDNA variants and cell types is unclear. In our systematic review, we sought to identify the biochemical threshold of mtDNA variants in relation to VAF by human tissue/cell type. We used controlled vocabulary terms to identify articles measuring oxidative phosphorylation (OXPHOS) complex activities in relation to VAF. We identified 76 eligible publications, describing 69, 12, 16, and 49 cases for complexes I, III, IV, and V, respectively. Few studies evaluated OXPHOS activities in diverse tissue types, likely reflective of clinical access. A number of cases with similar VAFs for the same pathogenic variant had varying degrees of residual activity of the affected complex, alluding to the presence of modifying variants. Tissues and cells with VAFs <60% associated with low complex activities were described, suggesting the possibility of a biochemical threshold of <60%. Using Kendall rank correlation tests, the VAF of the m.8993T > G variant correlated with complex V activity in skeletal muscle (τ = −0.58, P = 0.01, n = 13); however, no correlation was observed in fibroblasts (P = 0.7, n = 9). Our systematic review highlights the need to investigate the biochemical threshold over a wider range of VAFs in disease-relevant cell types to better define the biochemical threshold for specific mtDNA variants.

中文翻译：

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线粒体遗传变异生化阈值的系统评价

线粒体 DNA (mtDNA) 变异会导致一系列疾病，从严重的儿科综合症到衰老相关疾病。携带致病性变异的 mtDNA 拷贝的百分比，即变异等位基因频率 (VAF)，必须在生化缺陷发生之前达到阈值，称为生化阈值。经常引用的 >60% VAF 的生化阈值在 mtDNA 变体和细胞类型中是否相似尚不清楚。在我们的系统综述中，我们试图根据人体组织/细胞类型确定与 VAF 相关的 mtDNA 变异的生化阈值。我们使用受控词汇术语来识别测量与 VAF 相关的氧化磷酸化 (OXPHOS) 复合物活性的文章。我们确定了 76 篇符合条件的出版物，分别描述了复合体 I、III、IV 和 V 的 69、12、16 和 49 个病例。很少有研究评估 OXPHOS 在不同组织类型中的活性，这可能反映了临床可及性。许多具有相同致病性变异的相似 VAF 的病例具有不同程度的受影响复合物的残留活性，暗示修饰变异的存在。描述了 VAF <60% 的组织和细胞与低复合活性相关，这表明生化阈值 <60% 的可能性。使用 Kendall 等级相关性检验，m.8993T > G 变体的 VAF 与骨骼肌中复合 V 活性相关（τ = -0.58，P = 0.01，n = 13）；然而，在成纤维细胞中没有观察到相关性（P = 0.7，n = 9）。我们的系统综述强调需要研究疾病相关细胞类型中更广泛的 VAF 的生化阈值，以更好地定义特定 mtDNA 变异的生化阈值。