Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel
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.