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@ARTICLE{Meyer:284417,
      author       = {L. M. Meyer and S. E. Koschade$^*$ and J. B. Vischedyk and
                      M. Thoelken and A. Gubas and M. Wegner and M. Basoglu and S.
                      Knapp and M. Kaulich and S. Eimer and S. Shaid$^*$ and C. H.
                      Brandts$^*$},
      title        = {{D}eciphering the mitophagy receptor network identifies a
                      crucial role for {OPTN} (optineurin) in acute myeloid
                      leukemia.},
      journal      = {Autophagy},
      volume       = {19},
      number       = {11},
      issn         = {1554-8627},
      address      = {Abingdon, Oxon},
      publisher    = {Taylor $\&$ Francis},
      reportid     = {DKFZ-2023-02006},
      pages        = {2982 - 2996},
      year         = {2023},
      abstract     = {The selective autophagic degradation of mitochondria via
                      mitophagy is essential for preserving mitochondrial
                      homeostasis and, thereby, disease maintenance and
                      progression in acute myeloid leukemia (AML). Mitophagy is
                      orchestrated by a variety of mitophagy receptors whose
                      interplay is not well understood. Here, we established a
                      pairwise multiplexed CRISPR screen targeting mitophagy
                      receptors to elucidate redundancies and gain a deeper
                      understanding of the functional interactome governing
                      mitophagy in AML. We identified OPTN (optineurin) as sole
                      non-redundant mitophagy receptor and characterized its
                      unique role in AML. Knockdown and overexpression experiments
                      demonstrated that OPTN expression is rate-limiting for AML
                      cell proliferation. In a MN1-driven murine transplantation
                      model, loss of OPTN prolonged overall median survival by 7
                      days $(+21\%).$ Mechanistically, we found broadly impaired
                      mitochondrial respiration and function with increased
                      mitochondrial ROS, that most likely caused the proliferation
                      defect. Our results decipher the intertwined network of
                      mitophagy receptors in AML for both ubiquitin-dependent and
                      receptor-mediated mitophagy, identify OPTN as a
                      non-redundant tool to study mitophagy in the context of
                      leukemia and suggest OPTN inhibition as an attractive
                      therapeutic strategy.Abbreviations: AML: acute myeloid
                      leukemia; CRISPR: Clustered Regularly Interspaced Short
                      Palindromic Repeats; CTRL: control; DFP: deferiprone; GI:
                      genetic interaction; KD: knockdown; KO: knockout; ldMBM,
                      lineage-depleted murine bone marrow; LFC: log2 fold change;
                      LIR: LC3-interacting region; LSC: leukemic stem cell;
                      MAGeCK: Model-based Analysis of Genome-wide CRISPR-Cas9
                      Knockout; MDIVI-1: mitochondrial division inhibitor 1; MOI:
                      multiplicity of infection; MOM: mitochondrial outer
                      membrane; NAC: N-acetyl-L-cysteine; OA: oligomycin-antimycin
                      A; OCR: oxygen consumption rate; OE: overexpression; OPTN:
                      optineurin; PINK1: PTEN induced putative kinase 1; ROS:
                      reactive oxygen species; SEM: standard error of the mean;
                      TCGA: The Cancer Genome Atlas; TEM: transmission electron
                      microscopy; UBD: ubiquitin-binding domain; WT: wild type.},
      keywords     = {Animals / Mice / Mitophagy: genetics / Reactive Oxygen
                      Species: metabolism / Autophagy / Leukemia, Myeloid, Acute /
                      Ubiquitins / Ubiquitin-Protein Ligases: metabolism / AML
                      (Other) / MN1-driven mouse model (Other) / Mitochondrial ROS
                      (Other) / Multiplex CRISPR screen (Other) / genetic
                      interactions (Other) / leukemia (Other) / Reactive Oxygen
                      Species (NLM Chemicals) / Mdivi-1 (NLM Chemicals) /
                      Ubiquitins (NLM Chemicals) / Ubiquitin-Protein Ligases (NLM
                      Chemicals)},
      cin          = {FM01},
      ddc          = {570},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37439113},
      doi          = {10.1080/15548627.2023.2230839},
      url          = {https://inrepo02.dkfz.de/record/284417},
}