Mechanism of cardioprotective mitochondrial oxidative stress priming in doxorubicin-induced cardiotoxicity - PROJECT SUMMARY Mitochondria are essential for life because of their role in energy production and signaling functions that control redox homeostasis, inflammatory responses, and cell death. Accordingly, there is abundant evidence that mitochondrial dysfunction and oxidative stress drive cardiovascular disease pathogenesis, yet no mitochondrial or antioxidant therapies currently exist. Exposing mitochondria to some forms of stress initiates cytoprotective signaling programs that result in beneficial adaptations, a phenomenon called “mitohormesis”. Multiple benefits of mitohormesis have been documented including increased lifespan in invertebrate model organisms and, relevant to this proposal, protection against drug-induced liver injury through preservation of mitochondrial function in mice. However, how mitohormetic signaling functions in the heart has not been investigated. Therefore, the project goal is to test the potential for mitohormesis to protect against cardiac pathology and to identify the underlying signaling pathways through which it functions. Our lab has developed the first mouse model of oxidative mitohormesis, a form of mitohormesis that occurs in response to transient mitochondrial oxidative stress. These mice allow for inducible and reversible accumulation of superoxide, a form of mitochondrial reactive oxygen species (mtROS). Superoxide exposure only during embryogenesis results in mitohormesis in adult mouse liver characterized by increased basal antioxidant gene expression and mitochondrial biogenesis, and our preliminary data show the same is true in adult heart tissue. In addition, using a mouse embryonic fibroblast model of oxidative mitohormesis, transient mtROS exposure results in adapted cells that are protected against doxorubicin (DOXO)-induced oxidative stress and cell death. However, the mechanism driving this sustained protection is unknown. Mitochondrial superoxide inactivates the tricarboxylic acid cycle enzyme aconitase, leading to accumulation of its substrate citrate. Citrate can then be converted to acetyl-CoA, which is used for histone acetylation. In this proposal, I will test the central hypothesis that oxidative mitohormesis will protect against DOXO-induced cardiotoxicity (DIC), and that mitochondrial citrate mediates epigenetic remodeling that drives this adaptive signaling response. Since the cardiac toxicity of DOXO is mediated by increased mtROS production and decreased mitochondrial biogenesis, Aim 1 will determine if oxidative mitohormetic signaling can protect the heart in a chronic model of DIC. Aim 2A will uncover the mechanism by which the mitochondrial metabolite citrate regulates epigenetic-mediated changes in nuclear gene expression in response to oxidative mitohormesis, while Aim 2B will test whether citrate is sufficient to induce mitohormesis and protect against DIC in vivo. The long-term goal is to determine how mitohormetic signaling affects the response of cardiac tissue to oxidative and mitochondrial injury, a deeper understanding of which may uncover novel metabolites and signaling pathways with therapeutic potential for cardiac pathology and cardiovascular aging.
