Abstract
The PGC family of transcriptional co-activators (PGC-1α [Ppargc1a], PGC-1β [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.
Highlights
The PPAR-gamma coactivator (PGC) family of transcriptional co-activators have been called ‘master regulators’ of mitochondrial biogenesis because they co-activate the transcription factors nuclear respiratory factor-1 and -2 (NRF-1 (Nrf1), NRF-2 (Gabpa)), thereby initiating nuclear gene expression for mitochondrial proteins [1,2]
We report that Ppargc1a and Ppargc1b gene expression is negatively correlated with mir-202-3p, which is differently expressed in WT, TLR22/2, and TLR42/2 mice
This study examined the effects of acute S. aureus sepsis on the expression of the PGC family and other genes that regulate mitochondrial biogenesis in WT, TLR22/2, and TLR42/2 mice and had two major new findings
Summary
The PPAR-gamma coactivator (PGC) family of transcriptional co-activators have been called ‘master regulators’ of mitochondrial biogenesis because they co-activate the transcription factors nuclear respiratory factor-1 and -2 (NRF-1 (Nrf1), NRF-2 (Gabpa)), thereby initiating nuclear gene expression for mitochondrial proteins [1,2]. The known PGC family gene products (PGC1a (Ppargc1a), PGC-1b (Ppargc1b), and PRC (Pprc)) are variably affected by inflammation; for instance, Ppargc1a mRNA levels may decrease after exposure of cells to LPS, while PGC-1a protein content and stability are increased in mice exposed to LPS [3,4,5]. Mitochondrial damage in sepsis disrupts oxygen homeostasis, leading to a state of high tissue oxygenation but low tissue oxygen utilization sometimes called cytopathic hypoxia [8,9]. Increased mitochondrial damage and cytopathic hypoxia are correlated with a high mortality rate [10]. Sepsis is a growing health problem and a leading cause of death in the U.S, and despite aggressive intensive care, still has an in-hospital mortality rate of approximately 30% [11]
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