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  3. Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia

Deciphering the mitophagy receptor network identifies a crucial role for OPTN (optineurin) in acute myeloid leukemia

  • Autophagy. 2023 Jul 13;1-15. doi: 10.1080/15548627.2023.2230839.
Laura M Meyer 1 2,  Sebastian E Koschade 1 2 3,  Jonas B Vischedyk 1 2 3,  Marlyn Thoelken 1 2,  Andrea Gubas 4,  Martin Wegner 4,  Marion Basoglu 5,  Stefan Knapp 3 6,  Manuel Kaulich 3 4,  Stefan Eimer 5 7,  Shabnam Shaid 1 2 3,  Christian H Brandts 1 2 3
Affiliations

Affiliations

  • 1 Hematology and Oncology, Goethe University Frankfurt, University Hospital, Frankfurt, Germany.
  • 2 University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Frankfurt, Germany.
  • 3 Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Frankfurt, Germany.
  • 4 Institute of Biochemistry II, Goethe University Frankfurt, Frankfurt, Germany.
  • 5 Transmission-Electron Microscopy Core Facility, Goethe University Frankfurt, Frankfurt, Germany.
  • 6 Department of Biochemistry, Chemistry and Pharmacy, Institute for Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany.
  • 7 Institute for Cell Biology and Neuroscience, Goethe University Frankfurt, Frankfurt, Germany.
PMID: 37439113 DOI: 10.1080/15548627.2023.2230839
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

AML; MN1-driven mouse model; Mitochondrial ROS; Multiplex CRISPR screen; genetic interactions; leukemia.

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