Prohibitin coordinates an anti‐inflammatory/antioxidant feedback loop from mitochondria to nucleus to protect the heart from severe inflammatory stress

Abstract

Cardiovascular and mitochondrial dysfunctions are well‐known complications of sepsis. Prohibitin (PHB), a mitochondrial protein, has been implicated in experimental models involved in coordinating inflammatory signaling; its mechanisms are unknown. We investigated the role of PHB in the heart during sepsis using an in vivo model (LPS) and in vitro model (TNFα/IL1β) in HL1 cardiomyocytes (HL1c). Sepsis caused reductions in mitochondrial function in both models. In rats, LPS reduced PHB expression in whole heart at 4 and 24 hrs post exposure. While the total cardiac PHB decreased, serum levels spiked 3‐fold and the remainder became concentrated in nucleus. In vitro overexpression of PHB (oPHB) in HL1c attenuated the cytokine‐induced lowers O2 consumption, ATP generation, and Ca2+ retention, and prevented raises in H2O2 in response to these cytokines. oPHB protected the HL1c from TNFα/IL1β‐induced cytotoxicity. oPHB and recombinant PHB to HL1c reduced TNFα/IL1β‐induced NFκB activation and transcription of its downstream targets. These findings uncover a novel role for PHB and suggest that PHB can act as a mobile signal transducer which can suppress inflammation and oxidative stress during sepsis. We anticipate that these findings will lead to novel therapies that exploit the pleiotropic functions of PHB, protecting the heart from diseases in which inflammation and oxidative stress are common.