Mitochondrial superoxide–induced mitohormesis is mediated by citrate and cardioprotective
Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl–coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.
Authors
- Gladys R. Rojas
- Kathryn Lande (ORCID: https://orcid.org/0009-0005-1613-8981)
- Kailash Chandra Mangalhara (ORCID: https://orcid.org/0000-0001-7412-3095)
- Mack B. Reynolds (ORCID: https://orcid.org/0000-0002-8445-3749)
- Suzanne Dufresne (ORCID: https://orcid.org/0000-0003-2804-6791)
- Yuening Liu (ORCID: https://orcid.org/0000-0002-6891-0006)
- Pau B. Esparza‐Moltó (ORCID: https://orcid.org/0000-0001-9034-1121)
- Christian M. Metallo (ORCID: https://orcid.org/0000-0003-2404-3040)
- Allison Y. Louie (ORCID: https://orcid.org/0000-0001-9247-223X)
- Pallav Kosuri (ORCID: https://orcid.org/0000-0002-7025-3543)
- Åsa B. Gustafsson (ORCID: https://orcid.org/0000-0001-6347-8210)
- Neva Olliffe
- Alexandra G Moyzis (ORCID: https://orcid.org/0000-0002-3912-3660)
- Christina G. Towers (ORCID: https://orcid.org/0000-0003-0523-8096)
- Sagnika Ghosh (ORCID: https://orcid.org/0000-0003-2883-7008)
- Matthew P. Donnelly (ORCID: https://orcid.org/0000-0002-4667-8808)
- Gerald S. Shadel (ORCID: https://orcid.org/0000-0003-2899-8717)
- Melissa Johnson (ORCID: https://orcid.org/0000-0002-6913-6059)
- Diana C. Hargreaves (ORCID: https://orcid.org/0000-0003-3724-3826)
- Kym J. Grae
- Deann Guan
Institutions
- Salk Institute for Biological Studies (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- University of California San Diego (US)
- University of California San Diego Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1126/sciadv.aef8132
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fundación Alfonso Martín Escudero
- Chan Zuckerberg Initiative
- George E. Hewitt Foundation for Medical Research
- National Institutes of Health
- National Cancer Institute