Sepsis restructures the mitochondrial calcium uniporter complex in the lymphoid tissues of mice and humans.

Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca(2+)). During sepsis, mitochondrial dysfunction, a failure of Ca(2+) homeostasis, and sustained elevations in cytosolic [Ca(2+)] occur. These insults may serve as sufficient pressure to select for cells uniquely able to adapt. In this study of murine and human sepsis survivors, we observe that sepsis induces in lymphoid tissues a restructuring of the mitochondrial calcium uniporter (MCU) complex: the critical channel mediating the electrophoretic uptake of Ca(2+) into the mitochondrion. We show these changes persist after clinical resolution of sepsis and lead to alterations in mitochondrial Ca(2+) regulation, Ca(2+) signaling, oxidative metabolism, and sensitivity to programmed cell death pathways. These biochemical changes manifest as fundamental alterations in phenotype: i.e., heightened systemic IL-6 concentration. Inhibiting lysosomal pathways partially restores the MCU complex stoichiometry, mitochondrial Ca(2+) homeostasis, and lymphoid tissue phenotype to a sepsis naïve state.