Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation

Age-related cellular changes negatively impact CD4⁺ T cell function. Our prior work showed that mitochondrial complex II (succinate dehydrogenase [SDH]) expression was upregulated in T cells from older (O) adults (60-80 years old). T cells from older adults also produced higher amounts of cytokines generally considered proinflammatory, such as Th17 cytokines IL-17A/F and IL-21, and the Th-17-supportive cytokine IL-6, compared to T cells from younger (Y) adults (25-40 years old). The objective of our study is to evaluate whether hyperactivation of SDH is required for the induction of proinflammatory cytokines and the mechanistic link between SDH and Th17 cytokine production. CD4⁺ T cells were isolated from lean normoglycemic younger (avg: 31.58 years; BMI 21.14 kg/m²) and older (avg: 64.81 years; BMI 21.95 kg/m²) adults. SDH was pharmacologically and genetically modulated, and mitochondrial structure, function, metabolites, and cytokine production were quantified. SDH activation in T cells from older adults induced heightened oxidation of succinate, disrupted the fumarate-to-succinate ratio, stabilized HIF-1α, and promoted Th17 cytokines. Genetic and pharmacological inhibition of SDH in T cells from older adults lowered proinflammatory cytokine production, whereas exogenous addition of cell-permeable succinate induced SDH protein in T cells from younger adults and recapitulated the proinflammatory Th17 profile observed in T cells from older adults. These data establish a mechanistic link between SDH and Th17 inflammation.