Mechanism of mitochondria-induced myokine activation and implications for healthy aging. - PROJECT SUMMARY/ABSTRACT Excess body weight is a significant contributor to mortality rates in the United States, with class 2+ obesity increasing the risk of mortality by up to 91%. Physical activity plays a crucial role in managing prevalent diseases such as obesity, type 2 diabetes, and cardiovascular disease. Recently, exercise-stimulated myokines have been found to play a crucial role in inter-tissue signaling, promoting metabolic health and cardioprotection. However, the mechanism by which myokine expression is activated is poorly understood. Furthermore, therapeutically effective myokines are yet to be identified. Mitochondrial Precursor Overaccumulation Stress (mPOS) is a novel mediator of mitochondria-induced stress signaling, triggered by mitochondrial protein import stress and the accumulation of unimported mitochondrial proteins in the cytosol. In our preliminary study, we found the drastic activation of candidate myokines in a newly established mouse model of mPOS. This is accompanied with a strong lean phenotype and increased cardiac ejection fraction. These observations invited the hypothesis that mPOS may mediate myokine signaling, which ultimately promotes metabolic and cardiac health. In this predoctoral fellowship application, we will test the hypothesis that mitochondrial protein import stress can specifically induce myokine signaling by specific transcriptional factors in a bioenergetic-independent manner (Specific Aim 1). We will also test the hypothesis that mPOS-induced myokine release mediates fat loss and the improvement of cardiac health during aging (Specific Aim 2). Success of the proposed research represents a significant advancement in understanding mitochondria-induced myokine signaling and its potential implications for metabolic and cardiovascular health. Utilizing the murine and cell-based models, this study will uncover the mechanisms underlying myokine signaling and its impact on inter- tissue communication. These findings may lead to the discovery of novel health- promoting myokines and identification of therapeutic targets for metabolic and cardiovascular diseases, offering potential interventions to improve overall health, especially for aging populations and individuals unable to engage in physical exercise.
