The Mitochondrial Fission Regulator DRP1 Controls Post-Transcriptional Regulation of TNF-α

Abstract

The mitochondrial network plays a critical role in the regulation of innate immune signaling and subsequent production of proinflammatory cytokines such as IFN-β and IL-1β. Dynamin-related protein 1 (DRP1) promotes mitochondrial fission and quality control to maintain cellular homeostasis during infection. However, mechanisms by which DRP1 and mitochondrial dynamics control innate immune signaling and the proinflammatory response are incompletely understood. Here we show that macrophage DRP1 is a positive regulator of TNF-α production during sterile inflammation or bacterial infection. Silencing macrophage DRP1 decreased mitochondrial fragmentation and TNF-α production upon stimulation with lipopolysaccharide (LPS) or methicillin-resistant Staphylococcus aureus (MRSA) infection. The defect in TNF-α induction could not be attributed to changes in gene expression. Instead, DRP1 was required for post-transcriptional control of TNF-α. In contrast, silencing DRP1 enhanced IL-6 and IL-1β production, indicating a distinct mechanism for DRP1-dependent TNF-α regulation. Our results highlight DRP1 as a key player in the macrophage pro-inflammatory response and point to its involvement in post-transcriptional control of TNF-α production.

DRP1-Mediated Mitochondrial Fission Regulates the Lung Epithelial Response to Allergen

“…Though several studies have suggested DRP1 induces in ammatory signaling, here we show a link between DRP1 and suppression of HDM-induced proin ammatory cytokine and chemokine release by airway epithelia in culture. In agreement with our work, another study demonstrated DRP1 suppresses pro-in ammatory signaling in macrophages stimulated with LPS via regulation of release of mitochondrial damage-associated molecular patterns (DAMPs) (53).…”

DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

“…Though several studies have suggested DRP1 induces inflammatory signaling, here we show a link between DRP1 and suppression of HDM-induced pro-inflammatory cytokine and chemokine release by airway epithelia in culture. In agreement with our work, another study demonstrated DRP1 suppresses pro-inflammatory signaling in macrophages stimulated with LPS via regulation of release of mitochondrial damage-associated molecular patterns (DAMPs) [ 33 ]. Mitochondrial DAMPs play an important role in inflammatory signaling in response to lung injury [ 53 , 54 , 55 ].…”

“…One of the components of bacterial origin is lipopolysaccharide (LPS). LPS is known to induce DRP1 activation [ 32 , 33 , 34 ]. Therefore, we treated HBECs with LPS (0.6 ng/mL) at a level comparable to that found in the HDM used in our studies, as well as at a higher dose (100 ng/mL), to examine whether LPS alone is responsible for the DPR1 response induced by HDM.…”

“…LPS has been shown to upregulate DRP1 activation and mitochondrial fission in various lung cell types [ 32 , 33 , 34 ]. Although HDM contains LPS, our data suggest that HDM-induced DRP1 activation is not entirely reliant on its LPS content.…”

Mechanisms, Pathophysiology and Currently Proposed Treatments of Chronic Obstructive Pulmonary Disease

“…First, fission occurs through the inhibition of mitochondrial fusion protein. Second, the fission process demands the presence of mitochondrial fission, such as dynamin-related protein 1 (DRP1) [59], which interacts with human fission factor (Fis 1) and mitochondria fission factor (MFF). Thus, the extensive activation of DRP1 may increase mitochondrial fragmentation, increasing reactive oxygen species followed by decreased ATP production [60,61].…”