Department of Bioenergetics, Institute of Physiology Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Physiol Res. 2014;63(Suppl 1):S57-71. doi: 10.33549/physiolres.932643.
Disorders of ATP synthase, the key enzyme of mitochondrial energy provision belong to the most severe metabolic diseases presenting as early-onset mitochondrial encephalo-cardiomyopathies. Up to now, mutations in four nuclear genes were associated with isolated deficiency of ATP synthase. Two of them, ATP5A1 and ATP5E encode enzyme's structural subunits alpha and epsilon, respectively, while the other two ATPAF2 and TMEM70 encode specific ancillary factors that facilitate the biogenesis of ATP synthase. All these defects share a similar biochemical phenotype with pronounced decrease in the content of fully assembled and functional ATP synthase complex. However, substantial differences can be found in their frequency, molecular mechanism of pathogenesis, clinical manifestation as well as the course of the disease progression. While for TMEM70 the number of reported patients as well as spectrum of the mutations is steadily increasing, mutations in ATP5A1, ATP5E and ATPAF2 genes are very rare. Apparently, TMEM70 gene is highly prone to mutagenesis and this type of a rare mitochondrial disease has a rather frequent incidence. Here we present overview of individual reported cases of nuclear mutations in ATP synthase and discuss, how their analysis can improve our understanding of the enzyme biogenesis.
三磷酸腺苷合酶（ATP synthase）是线粒体能量供应的关键酶，其相关缺陷属于代谢性疾病中最严重的一类，可导致早发型线粒体脑肌病。迄今为止，已有 4 个核基因突变与 ATP 合酶的单一缺陷相关，其中 2 个（ATP5A1 和 ATP5E）编码酶的结构亚基 α和 ε，另外 2 个（ATPAF2 和 TMEM70）编码特定的辅助因子，协助 ATP 合酶的生物发生。所有这些缺陷具有相似的生化表型，即完全组装和功能正常的 ATP 合酶复合物含量明显降低。然而，它们在频率、发病分子机制、临床表现和疾病进展方面存在显著差异。虽然 TMEM70 相关突变的报道病例数和突变谱在不断增加，但 ATP5A1、ATP5E 和 ATPAF2 基因突变非常罕见。显然，TMEM70 基因非常容易发生突变，这种罕见的线粒体疾病具有较高的发病率。本文概述了 ATP 合酶核基因突变的个别报道病例，并讨论了对这些突变的分析如何有助于加深对酶生物发生的理解。
