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 Cells were grown to 2x10^7 cells/mL as described in YEP-Raffinose and 500 µL were pelleted and stored at -80°C. RNA was extracted using the miRNeasy Mini Kit (Qiagen, #217004) according to manufacturer instructions. Briefly, cells were lysed in a bead miller with acid-washed glass beads and Qiagen Buffer RLT. One volume of 70% ethanol was added to the homogenized lysate and the sample was purified using the RNeasy spin column and eluted in RNAse-free water. The cDNA library preparation and sequencing were conducted by Novogene using a paired-end 150 bp sequencing strategy on the Illumina NovaSeq 6000 platform.