bims-mikwok 2023-05-14 papers

Issue of 2023‒05‒14
two papers selected by
Avinash N. Mukkala, University of Toronto

EMBO J. 2023 May 10. e112767

FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.

Giang Thanh Nguyen-Dien, Keri-Lyn Kozul, Yi Cui, Brendan Townsend, Prajakta Gosavi Kulkarni, Soo Siang Ooi, Antonio Marzio, Nissa Carrodus, Steven Zuryn, Michele Pagano, Robert G Parton, Michael Lazarou, S Sean Millard, Robert W Taylor, Brett M Collins, Mathew Jk Jones, Julia K Pagan.

To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4 , an SKP1/CUL1/F-box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4-associated mtDNA depletion syndrome.

Keywords: BNIP3; FBXL4; NIX/BNIP3L; mitochondria; mitophagy

DOI: https://doi.org/10.15252/embj.2022112767

Ann Surg. 2023 May 08.

DANGER Signals Activate G-Protein Receptor Kinases Suppressing Neutrophil Function and Predisposing to Infection After Tissue Trauma.

Hyo In Kim, Jinbong Park, David Gallo, Sidharth Shankar, Barbora Konecna, Yohan Han, Valerie Banner-Goodspeed, Krystal R Capers, Seong-Gyu Ko, Leo E Otterbein, Kiyoshi Itagaki, Carl J Hauser.

OBJECTIVE: Surgery injures tissue and predisposes to local and systemic infections. We studied injury-induced immune dysfunction seeking novel means to reverse such predisposition.BACKGROUND: Injury mobilizes primitive 'DANGER signals' (DAMPs) activating innate immunocyte (neutrophils, PMN) signaling and function. Mitochondrial (mt) formyl peptides (FP) activate G-protein coupled receptors (GPCR) like FPR1. mtDNA and heme activate toll-like receptors (TLR9, TLR2/4). GPCR kinases (GRKs) can regulate GPCR activation.
METHODS: We studied human and mouse PMN signaling elicited by mtDAMPs (GPCR surface expression; protein phosphorylation or acetylation; Ca2+ flux) and antimicrobial functions (cytoskeletal reorganization, chemotaxis (CTX), phagocytosis, bacterial killing) in cellular systems and clinical injury samples. Predicted rescue therapies were assessed in cell systems and mouse injury-dependent pneumonia models.
RESULTS: mtFPs activate GRK2, internalizing GPCRs and suppressing CTX. mtDNA suppresses CTX, phagocytosis and killing via TLR9 through a novel, non-canonical mechanism that lacks GPCR endocytosis. Heme also activates GRK2. GRK2 inhibitors like paroxetine restore functions. GRK2 activation via TLR9 prevented actin reorganization, implicating histone deacetylases (HDACs). Actin polymerization, CTX, bacterial phagocytosis and killing were also rescued therefore by the HDAC inhibitor valproate. Trauma repository PMN showed GRK2 activation and cortactin deacetylation which varied with severity and was most marked in patients developing infections. Either GRK2 or HDAC inhibition prevented loss of mouse lung bacterial clearance, but only the combination rescued clearance when given post-injury.
CONCLUSIONS: Tissue injury-derived DAMPs suppress antimicrobial immunity via canonical GRK2 activation and a novel TLR-activated GRK2 pathway impairing cytoskeletal organization. Simultaneous GRK2/HDAC inhibition rescues susceptibility to infection after tissue injury.

DOI: https://doi.org/10.1097/SLA.0000000000005898