Mitochondrial dynamics regulates iron homeostasis and nuclear genome stability [RNA-seq]

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，并对能量生成与细胞健康发挥调节作用。人类线粒体动力学异常与视神经萎缩、神经病变、心肌病或痴呆症密切相关。本研究通过对核基因组中模板插入序列（templated insertions, TINS）水平升高的酵母突变体进行筛选，鉴定出线粒体融合缺陷突变体（mgm1、ugo1、fzo1）。研究发现，融合缺陷突变体会激活铁调节子（iron regulon），导致铁硫簇（iron-sulfur clusters, ISC）水平下降与DNA损伤增加，这提示铁稳态在抑制TINS形成中发挥重要作用。与之一致的是，二次筛选结果显示，多种铁稳态突变体均表现出高水平的TINS。本研究提出，铁稳态失调引发氧化性DNA损伤，加之DNA修复功能受损，共同推动了TINS的产生。通过提升线粒体膜电位，可缓解融合缺陷突变体的生长不良、铁稳态失衡与基因组不稳定性问题，这为相关治疗提供了全新思路。本系列研究将线粒体动力学与铁稳态失衡及基因组稳定性关联起来。