Mitochondrial Aco2 Inhibition and Citrate Export Drive Epigenetic Adaptations in Mitohormesis

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Summary of  Science Advances  https://doi.org/10.1126/sciadv.aef8132
Dr. Matthew P. Donnelly et al.

Points

Salk Institute researchers demonstrated that transient embryonic mitochondrial stress activates protective mitohormetic signaling pathways that safeguard adult cardiac tissue against oxidative damage.
Superoxide accumulation during embryonic development conferred lasting resilience in adult mice subjected to doxorubicin chemotherapy, preventing cardiac failure and pathological structural remodeling.
In vitro cell assays demonstrated that mitochondrial superoxide accumulation inhibits aconitase activity, causing intracellular citrate accumulation and subsequent export into the cytoplasm.
Cytosolic citrate conversion into acetyl-CoA drives targeted histone acetylation, establishing durable epigenetic modifications that upregulate cellular antioxidant systems and organelle biogenesis.
Direct citrate supplementation or Aco2 gene silencing successfully replicated these protective adaptations, highlighting mitohormetic signaling as a potential target for age-related tissue pathology.

Summary

This study evaluated the molecular mechanisms of mitohormesis, wherein transient mitochondrial stress drives adaptive signaling to enhance organelle biogenesis and cellular resilience. Led by Gerald Shadel at the Salk Institute and published in Science Advances, the investigation explored how embryonic superoxide stress reprograms the mammalian heart and whether metabolic signaling pathways can confer long-term cardioprotection. Given that high reactive oxygen species (ROS) concentrations induce cellular injury while lower levels serve as essential signaling triggers, the research sought to identify downstream epigenetic mediators that connect early mitochondrial ROS signaling with adult organ preservation.

Using a transgenic mouse model, researchers transiently inhibited mitochondrial antioxidant defenses during embryonic development, subsequently restoring normal enzyme function before birth. Upon reaching adulthood, the mice were exposed to doxorubicin-induced cardiotoxicity to evaluate structural and functional outcomes. Embryonic superoxide accumulation successfully protected adult cardiac tissue against doxorubicin-induced mitochondrial degradation, preventing adverse cardiac remodeling and heart failure. Mechanistic evaluations in embryonic fibroblasts demonstrated that superoxide accumulation inhibits mitochondrial aconitase, triggering mitochondrial citrate accumulation and cytosolic export, where it is converted into acetyl-CoA to drive protective histone acetylation.

Preventing mitochondrial citrate export completely abolished these protective adaptive changes, whereas direct citrate supplementation or Aco2 gene silencing fully recapitulated the mitohormetic phenotype. The findings confirm that mitochondrial citrate acts as a redox-sensitive second messenger linking early ROS signaling to durable epigenetic remodeling. The authors conclude that targeting mitohormetic pathways and citrate signaling represents a promising therapeutic approach to mitigate doxorubicin cardiotoxicity, attenuate age-related organ dysfunction, and improve long-term cardiovascular health.

Link to the article: https://www.science.org/doi/10.1126/sciadv.aef8132

References

Donnelly, M. P., Mangalhara, K. C., Liu, Y., Lande, K., Rojas, G. R., Grae, K. J., Reynolds, M. B., Ghosh, S., Olliffe, N., Esparza-Moltó, P. B., Johnson, M. A., Dufresne, S., Louie, A. Y., Moyzis, A. G., Guan, D., Gustafsson, Å. B., G. Towers, C., Kosuri, P., Metallo, C. M., … Shadel, G. S. (2026). Mitochondrial superoxide–induced mitohormesis is mediated by citrate and cardioprotective. Science Advances, 12(36), eaef8132. https://doi.org/10.1126/sciadv.aef8132