The “theory of resistant biomolecules” posits that long-lived species show resistance to molecular damage at the level of their biomolecules. Here, we test this hypothesis in the context of mitochondrial DNA (mtDNA) as it implies that predicted mutagenic DNA motifs should be inversely correlated with species maximum lifespan (MLS).

First, we confirmed that guanine-quadruplex and direct repeat (DR) motifs are mutagenic, as they associate with mtDNA deletions in the human major arc of mtDNA, while also adding mirror repeat (MR) and intramolecular triplex motifs to a growing list of potentially mutagenic features. What is more, triplex motifs showed disease-specific associations with deletions and an apparent interaction with guanine-quadruplex motifs.

Surprisingly, even though DR, MR and guanine-quadruplex motifs were associated with mtDNA deletions, their correlation with MLS was explained by the biased base composition of mtDNA. Only triplex motifs negatively correlated with MLS even after adjusting for body mass, phylogeny, mtDNA base composition and effective number of codons.

Taken together, our work highlights the importance of base composition for the comparative biogerontology of mtDNA and suggests that future research on mitochondrial triplex motifs is warranted.

“抗性生物分子理论”假定长寿物种在其生物分子水平上表现出对分子损伤的抵抗力。在这里，我们在线粒体 DNA (mtDNA) 的背景下测试这一假设，因为它意味着预测的诱变 DNA 基序应该与物种最大寿命 (MLS) 成反比。

首先，我们证实鸟嘌呤四链体和同向重复 (DR) 基序具有致突变性，因为它们与人类 mtDNA 主弧中的 mtDNA 缺失相关，同时还将镜像重复 (MR) 和分子内三链体基序添加到越来越多的潜在诱变特征。更重要的是，三链体基序显示出与缺失的疾病特异性关联以及与鸟嘌呤-四链体基序的明显相互作用。

令人惊讶的是，尽管 DR、MR 和鸟嘌呤四链体基序与 mtDNA 缺失相关，但它们与 MLS 的相关性可以通过 mtDNA 的偏向碱基组成来解释。即使在调整体重、系统发育、mtDNA 碱基组成和有效密码子数后，也只有三重基序与 MLS 呈负相关。

总之，我们的工作强调了碱基组成对 mtDNA 比较生物老年学的重要性，并表明未来对线粒体三链体基序的研究是有必要的。