Mitochondrial Aging Promotes Inflammation

PROJECT SUMMARY/ABSTRACT Mitochondrial Aging Promotes Inflammation Aging is often associated with a progressive decline in health, resulting in reduced quality of life that limits health span, defined as the number of years spent in good health. Of the many cellular processes that decline with age, changes in the mitochondria are significant because numerous studies show a link between altered mitochondrial function and the development of age-associated diseases. Our data, supported by the current R15 award, show that aging promotes an increase in the localization of STAT3 to the mitochondria (mitoSTAT3), which induces profound changes in mitochondrial structure, dynamics, and function and has a mechanistic link to proinflammatory Th17 cytokine production. Th17 cytokines (IL-17A, IL-17F, IL-21) and Th17 supportive cytokines (IL6, TNFα) are specifically known to promote age-associated diseases such as diabetes, several forms of autoimmunity, cancers, and neuropathology such as Alzheimer’s and dementia. Specifically, mitoSTAT3 increased the OXPHOS dependence of aging T cells due to its effect on mitochondrial complex II; succinate dehydrogenase (SDH). Limiting mitoSTAT3 using mitochondria-targeted STAT3 inhibitor, Mtcur-1, lowered complex II expression and activity, prevented age-induced changes in mitochondrial structure, dynamics, and function, and reduced proinflammatory Th17 inflammation. Exogenous expression of the constitutive serine phosphorylated form of STAT3, a required phosphorylation for mitochondrial translocation, in T cells from young adults mimicked changes in mitochondrial function in T cells from older adults and promoted the production of Th17 supportive cytokines. The data also showed the involvement of additional key factors that support Th17 inflammation along with mitoSTAT3. The proposed work will comprehensively evaluate the mechanisms that regulate mitoSTAT3 and the role of succinate dehydrogenase in CD4+ T cell inflammation during aging.