Summary: Researchers at the University of Queensland have identified an anti-aging role for a mitochondrial protein called ATFS-1. This protein helps cells balance the competing needs of producing new mitochondria and repairing damaged mitochondrial DNA, a balance that affects cellular health and functional aging.
In laboratory studies using the model organism Caenorhabditis elegans (roundworms), enhancing ATFS-1 activity improved measures of cellular health and preserved physical function as the animals aged. While lifespan itself did not increase, the quality of aging—how well tissues and organs perform—showed measurable improvement. These findings suggest potential avenues for protecting mitochondrial DNA and supporting healthy aging in humans, as well as for treating inherited mitochondrial diseases.
Key Facts:
- ATFS-1 is a regulator that shifts mitochondrial activity toward DNA repair instead of transcription when mtDNA is damaged.
- Experimental enhancement of ATFS-1 function in C. elegans improved cellular health and delayed declines in movement and behavior associated with aging.
- Because mitochondrial dysfunction contributes to many age-related conditions, including some neurodegenerative diseases, manipulating ATFS-1 or its pathway could inform therapies to maintain organ function during aging.
Source: University of Queensland
Discovery at the University of Queensland
Associate Professor Steven Zuryn and Dr Michael Dai at the Queensland Brain Institute have shown that the transcription factor ATFS-1 occupies a key control point inside cells. ATFS-1 helps determine whether mitochondria focus on expressing their genome (transcription) or on repairing damaged mitochondrial DNA (mtDNA). Because mitochondria generate cellular energy but also produce reactive by-products that damage mtDNA, the choice between transcription and repair has long-term consequences for cell function and organismal health.
Under stress or when mtDNA sustains damage, ATFS-1 redirects mitochondrial activity toward repair processes. Dr Zuryn used a pit-stop analogy: when mitochondria are damaged, ATFS-1 signals that a repair “pitstop” is needed to restore function rather than continuing full-speed operation.
In experiments on C. elegans, increasing ATFS-1 activity led to improved cellular resilience. The worms maintained greater agility and behavioral function as they aged, demonstrating enhanced “healthy aging” without necessarily extending total lifespan. This distinction—preserving function rather than increasing longevity—is especially important for clinical goals that aim to improve quality of life in older adults.
“In conditions of stress, when mitochondrial DNA has been damaged, the ATFS-1 protein prioritises repair which promotes cellular health and longevity,” Dr Zuryn said. “We studied ATFS-1 in C. elegans and saw that enhancing its function promoted cellular health, meaning the worms became more agile for longer. They didn’t live longer, but they were healthier as they aged.”
Dr Zuryn and colleagues emphasize that mitochondrial dysfunction is central to many human diseases, including age-related neurodegenerative disorders. Their work suggests that modulating the balance between mtDNA transcription and repair could help maintain tissue and organ performance that typically declines with age.
“Our goal is to prolong the tissue and organ functions that typically decline during aging by understanding how deteriorating mitochondria contribute to this process,” Dr Michael Dai said. “We may ultimately design interventions that keep mitochondrial DNA healthier for longer, improving our quality of life.”
About this aging and genetics research news
Author: Lisa Clarke
Source: University of Queensland
Contact: Lisa Clarke – University of Queensland
Image: The image is credited to Neuroscience News
Original Research: Closed access. Title: “ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.” Published in Nature Cell Biology by Steven Zuryn et al.
Abstract
ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription
Balancing competing functional demands is essential for organismal survival. Transcription and repair of the mitochondrial genome (mtDNA) require distinct enzymatic activities that can sterically interfere with one another, implying a trade-off between genome expression and maintenance throughout life. In Caenorhabditis elegans, the bZIP transcription factor ATFS-1/Atf5 regulates this balance in favor of mtDNA repair by localizing to mitochondria and disrupting assembly of the mitochondrial pre-initiation transcription complex formed by HMG-5/TFAM and RPOM-1/mtRNAP.
By inhibiting transcription within mitochondria, ATFS-1 reduces age-dependent accumulation of mtDNA damage through mechanisms that involve the DNA glycosylase NTH-1/NTH1 and the helicase TWNK-1/TWNK. This shift toward repair enhances functional longevity at the cellular level and protects against behavioral decline caused by targeted and severe mtDNA damage.
Collectively, these findings position ATFS-1 as a molecular hub that controls the trade-off between mitochondrial genome expression and maintenance, with implications for healthy aging and mitochondrial disease.