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 (Ca2+). During sepsis,
mitochondrial dysfunction, a failure of Ca2+ homeostasis, and sustained
elevations in cytosolic [Ca2+] occur. These insults may serve as
sufficient pressure to select for cells uniquely able to adapt. In this
study, we compare the spleen and bone marrow lymphoid tissues of murine
and human survivors of intraabdominal sepsis and non-sepsis critical
illness (i.e., sterile trauma). 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 Ca2+
into the mitochondrion. We show these changes persist after clinical
resolution of sepsis and lead to alterations in mitochondrial Ca2+
regulation, Ca2+ 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 Ca2+ homeostasis, and lymphoid tissue
phenotype to a sepsis naïve state.