Mitochondrial-encoded immunity in restoring macrophage homeostasis under age-related metabolic stress

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PROJECT SUMMARY Age-dependent metabolic dysfunction is associated with maladaptive immune responses. Mitochondria are key metabolic organelles that are also capable of activating innate immune signaling. Components of the mitochondria, such as mitochondrial DNA (mtDNA) itself, can trigger immune responses; however, there are currently no known immunomodulators encoded in the mitochondrial genome. MOTS-c is a peptide encoded in the mitochondrial genome that we previously characterized as a regulator of metabolic homeostasis during aging. MOTS-c treatment increases lipid metabolism and prevents diet-induced obesity, fatty liver, and age- dependent physical decline in mice. Our preliminary data indicate that MOTS-c is induced during monocyte activation and translocates to the nucleus to regulate gene expression and reprogram the differentiation of monocytes into macrophages. This suggests that MOTS-c has a crucial role in regulating immune function. Because MOTS-c regulates responses to metabolic stress and modulates macrophage phenotype, I hypothesize that MOTS-c will enhance the adaptive capacity of macrophages to maintain homeostasis during age-related lipid stress. During age- and diet-induced metabolic dysregulation, total cholesterol and triglyceride levels increase in tissue and in circulation. These lipids can induce maladaptive responses in monocyte-derived macrophages that promote chronic sterile inflammation. Here, I will test 1) the role of MOTS- c in preventing maladaptive reprogramming of monocyte-derived macrophages differentiated with lipid stress, and 2) whether MOTS-c treatment in aged and high-fat diet fed mice prevents macrophage maladaptation and tissue damage in the liver associated with chronic inflammation. Collectively, these experiments will test the paradigm-shifting concept that immunity is encoded in both of our co-evolved mitonuclear genomes. This research, if successful, has broad therapeutic applications in the treatment of age-related chronic inflammatory diseases.