Brucella abortus induces dynamin-related protein 1 (DRP1)–dependent mitochondrial fission in infected macrophages via stress sensor IRE1α altering metabolic function
Year: 2025
Type: article
Abstract: Brucella abortus exploits the endoplasmic reticulum as a site for replication, triggering the unfolded protein response (UPR). While various pathogens have developed strategies to manipulate mitochondrial dynamics, the mechanisms underlying bacterial infection and mitochondrial dynamics interactions remain poorly understood. Here, we demonstrate that B. abortus induces mitochondrial fragmentation via IRE1α. Our findings reveal that Brucella-induced mitochondrial fission is mediated by dynamin-related protein 1 (DRP1), a pivotal regulator of mitochondrial fission. Moreover, we have demonstrated that DRP1 is activated by the UPR. Brucella-induced fragmentation leads to mitochondrial energetic dysfunction, marked by impaired mitochondrial ATP production and compromised bioenergetic capacity. Furthermore, we reveal a novel role for DRP1 in regulating type I IFN production and signaling during B. abortus infection. Mechanistically, mitochondrial fission facilitates the release of mitochondrial DNA, a potent inducer of type I IFN responses. Despite its impact on mitochondrial function and IFN signaling, DRP1 does not influence the control of B. abortus infection. Our findings uncover a unique mechanism by which B. abortus-induced UPR triggers mitochondrial fragmentation affecting innate immune signaling and cellular metabolism.
Source: The Journal of Immunology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: The role of STING and the unfolded protein response on macrophage polarization and control of Brucella abortus infection, G4331094672, G4809180745, Study of the mechanisms responsible for trained immunity induced by Bacillus Calmette-Guérin (BCG) in infectious diseases and Cancer, Multi-user equipment approved in grant 2023/02577-5: Amersham Imagequant 800, G8894740887, Brucella induces STING-mediated Guanylate-Binding Protein expression and Unfolded Protein Response: Balancing Bacterial Elimination, Inflammation and Disease, Anti-inflammatory Activity of a Systemic STING Inhibitory Non-Nucleotide
OpenAlex ID: W4413139197