Adipocyte-specific mitochondrial intermediate peptidase (Mipep) deficiency protects against LPS-induced lethal inflammation through GDF15- and FGF21-independent mechanisms

Abstract Sepsis is a life-threatening organ failure driven by an abnormally uncontrollable inflammatory response to systemic infection. Recent studies have demonstrated that mild mitochondrial stress confers protection against lipopolysaccharide (LPS)-induced septic shock; however, the precise mechanisms linking mitochondrial dysfunction to sepsis tolerance remain elusive. Here, we demonstrate that adipocyte-specific knockout of mitochondrial intermediate peptidase (MIPEP), termed aMKO, reduces susceptibility to LPS-induced mortality in mice. In MIPEP-deficient white adipose tissue (WAT), LPS-induced inflammatory responses were not uniform; selected proinflammatory and inflammasome-related responses were enhanced. By contrast, Mipep deficiency blunted the LPS-induced increase in circulating inflammatory cytokines. Consistent with this systemic attenuation, LPS-induced inflammatory cytokine expression was also less pronounced in nontargeted organs, including the liver, lungs, and spleen, where MIPEP remains intact. Although mitochondrial stress induces expression of growth differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21), which have been implicated in LPS tolerance, neither GDF15 deficiency nor pharmacological inhibition of FGF receptors affected the LPS resistance acquired in aMKO mice. Together, these findings suggest that MIPEP deficiency-induced remodeling of WAT inflammatory responses attenuates LPS-induced systemic cytokine amplification and lethal inflammation through mechanisms not fully dependent on endogenous GDF15 or FGF21.