Logo image
Back
Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1
Journal article   Open access   Peer reviewed

Evolutionarily Conserved but Mechanistically Distinct Mitochondrial Responses to Loss of Timeless/Swi1

Kalisse Horne, Joshua Chang Mell, Chiaki Noguchi, Sri Havya Jana, Shriya Pinisetty, Rhea Masand, Christian Sell and Eishi Noguchi
Biomolecules, v 16(8), 1177
12 Aug 2026
DOI: https://doi.org/10.3390/biom16081177
PMID: 42650843
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
url
https://doi.org/10.3390/biom16081177View
Published, Version of Record (VoR) Open Access Discount via Drexel Libraries Read and Publish Program 2026 Open CC BY V4.0

Abstract

Timeless Swi1 fission yeast <italic>Schizosaccharomyces pombe</italic> mitochondria mtDNA DNA polymerase gamma stress response mitochondrial genome oxidative stress
Timeless and its fission yeast ortholog Swi1 are evolutionarily conserved components of the replication fork protection complex that ensures faithful DNA replication and genome stability. While their nuclear roles are well-characterized, their roles in mitochondrial genome maintenance remain unknown. Here, we demonstrate a previously unrecognized connection between Timeless/Swi1 and mitochondrial homeostasis. In fission yeast, swi1 deletion increased association of the DNA repair protein Rad52 with mitochondrial DNA sequences across the mitochondrial genome, suggesting altered mitochondrial genome maintenance. Unexpectedly, swi1∆ cells showed an increased mtDNA copy number and improved growth under respiratory conditions, suggesting activation of compensatory mechanisms that promote mitochondrial genome maintenance. The loss of Swi1 also partially rescued the growth defect under respiratory conditions and mtDNA loss associated with depletion of mitochondrial DNA polymerase γ, linking Swi1 to pathways regulating mitochondrial replication under stress. Consistent with these phenotypes, transcriptomic and pathway enrichment analyses revealed transcriptional changes indicative of reduced glycolysis and enhanced oxidative phosphorylation, suggesting a shift toward respiratory metabolism. In human cells, Timeless depletion elicited distinct mitochondrial responses depending on the cell type. While Timeless-depleted TE-11 and Saos-2 cells elicited mitochondrial phenotypes comparable to those observed in fission yeast, Timeless depletion in U-2 OS cells led to reduced mtDNA copy number, elevated mitochondrial reactive oxygen species, and decreased mitochondrial membrane potential and mass, consistent with mitochondrial dysfunction. Despite these phenotypic differences, both fission yeast and human cells exhibited elevated levels of orthologs of the mitochondrial transcription factor A (TFAM) and the oxidative stress regulator NRF2, suggesting the conserved activation of compensatory mitochondrial and antioxidant pathways. Together, these findings identify an evolutionarily conserved connection between Timeless/Swi1 and mitochondrial homeostasis and reveal distinct adaptive responses to mitochondrial stress.

Metrics

3 Record Views

Details

Logo image