Deficits in mitochondrial dynamics and iron balance result in templated insertions

Jordan Fox, Yang Yu, Yang Yu, Pilendra Thakre, Chloe Fox, Qian Li, Yunxia Wang, Adam Hughes, Xin Wang (), Kaifu Chen () and Grzegorz Ira ()
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Jordan Fox: Baylor College of Medicine
Yang Yu: Boston Children’s Hospital
Yang Yu: Baylor College of Medicine
Pilendra Thakre: Baylor College of Medicine
Chloe Fox: Baylor College of Medicine
Qian Li: Baylor College of Medicine
Yunxia Wang: Boston Children’s Hospital
Adam Hughes: University of Utah School of Medicine
Xin Wang: Boston Children’s Hospital
Kaifu Chen: Boston Children’s Hospital
Grzegorz Ira: Baylor College of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. In a screen for yeast mutants with increased levels of templated insertions (~10-1000 bp) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1Δ, ugo1Δ, fzo1Δ). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISCs), and increased DNA damage, suggesting a role of iron homeostasis in preventing insertions. Consistently, a secondary screen found mutants affecting iron-sulfur cluster production (yfh1Δ, grx5Δ), vacuolar iron storage (ccc1Δ) or general iron homeostasis (aft1Δ) to exhibit high insertion levels. Treatment with iron chelators or hydrogen peroxide also increased insertions. We propose that iron dysregulation leading to oxidative DNA damage and compromised DNA repair drives insertions. These studies suggest that severe iron imbalance, associated with many human diseases and pharmacological treatments, can trigger genome instability in the form of templated insertions.

Date: 2025
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DOI: 10.1038/s41467-025-60546-2

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