Mitochondrial dynamics regulates iron homeostasis and nuclear genome stability

Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. Defective mitochondrial dynamics in humans are related to optic atrophy, neuropathies, cardiomyopathies, or dementia. In a screen for yeast mutants with increased levels of templated insertions (TINS) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1, ugo1, fzo1). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISC) and increased DNA damage, suggesting a role of iron homeostasis in preventing TINS. Consistently, a secondary screen found many iron homeostasis mutants to exhibit high TINS. We propose that iron dysregulation leading to oxidative DNA damage coupled with compromised DNA repair drives TINS. Poor growth, iron dyshomeostasis, and genome instability can be suppressed in fusion mutants by increasing mitochondrial membrane potential, suggesting a new therapeutic approach. These studies link mitochondrial dynamics to iron homeostasis deficiency and genome stability线粒体膜动力学（mitochondrial membrane dynamics）调控线粒体的形态、数量与分布，并参与能量产生及细胞健康状态的维持。人体中线粒体膜动力学缺陷与视神经萎缩、神经病变、心肌病或痴呆密切相关。在针对核基因组内模板化插入（Templated Insertions, TINS）水平升高的酵母突变体的筛选实验中，我们鉴定出了线粒体融合缺陷突变体（mgm1、ugo1、fzo1）。研究发现，此类融合缺陷突变体可激活铁调节子，其铁硫簇（Iron-Sulfur Clusters, ISC）含量降低且DNA损伤程度升高，这提示铁稳态在预防TINS发生中发挥关键作用。与之相一致的是，二次筛选发现诸多铁稳态突变体均表现出高水平的TINS。我们提出，铁稳态失调引发氧化性DNA损伤，再结合受损的DNA修复过程，共同推动了TINS的产生。线粒体融合缺陷突变体所出现的生长不良、铁稳态失衡与基因组不稳定性，可通过提升线粒体膜电位得到缓解，这为相关治疗提供了全新的潜在策略。上述研究将线粒体膜动力学与铁稳态缺陷及基因组稳定性建立了关联。