Differential regulation of the PGC family of genes in a mouse model of Staphylococcus aureus sepsis.
The PGC family of transcriptional co-activators (PGC-1alpha [Ppargc1a], PGC-1beta [Ppargc1b], and PRC [Pprc]) coordinates the upregulation of mitochondrial biogenesis, and Ppargc1a is known to be activated in response to mitochondrial damage in sepsis. Therefore, we postulated that the PGC family is regulated by the innate immune system. We investigated whether mitochondrial biogenesis and PGC gene expression are disrupted in an established model of Staphylococcus aureus sepsis both in mice with impaired innate immune function (TLR2-/- and TLR4-/-) and in wild-type controls. We found an early up-regulation of Ppargc1a and Ppargc1b post-infection (at 6 h) in WT mice, but the expression of both genes was concordantly dysregulated in TLR2-/- mice (no increase at 6 h) and in TLR4-/- mice (amplified at 6 h). However, the third family member, PRC, was regulated differently, and its expression increased significantly at 24 h in all three mouse strains (WT, TLR2-/-, and TLR4-/-). In silico analyses showed that Ppargc1a and Ppargc1b share binding sites for microRNA mmu-mir-202-3p. Thus, miRNA-mediated post-transcriptional mRNA degradation could account for the failure to increase the expression of both genes in TLR2-/- mice. The expression of mmu-mir-202-3p was measured by real-time PCR and found to be significantly increased in TLR2-/- but not in WT or TLR4-/- mice. In addition, it was found that mir-202-3p functionally decreases Ppargc1a mRNA in vitro. Thus, both innate immune signaling through the TLRs and mir-202-3p-mediated mRNA degradation are implicated in the co-regulation of Ppargc1a and Ppargc1b during inflammation. Moreover, the identification of mir-202-3p as a potential factor for Ppargc1a and Ppargc1b repression in acute inflammation may open new avenues for mitochondrial research and, potentially, therapy.
Sweeney, TE; Suliman, HB; Hollingsworth, JW; Piantadosi, CA
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