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In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy
  • Bojana Kravic, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Angelika B. Harbauer, Universität Freiburg im Breisgau
  • Vanina Romanello, Università degli Studi di Padova
  • Luca Simeone, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • F. Nora Vögtle, Universität Freiburg im Breisgau
  • Tobias Kaiser, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Marion Straubinger, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Danyil Huraskin, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Martin Böttcher, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Cristina Cerqua, Università degli Studi di Padova
  • Eva Denise Martin, St Thomas' Hospital
  • Daniel Poveda-Huertes, Universität Freiburg im Breisgau
  • Andreas Buttgereit, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Adam J. Rabalski, The University of Western Ontario
  • Dieter Heuss, Universitätsklinik Erlangen und Medizinische Fakultät
  • Rüdiger Rudolf, Hochschule Mannheim
  • Oliver Friedrich, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • David Litchfield, The University of Western Ontario
  • Michael Marber, St Thomas' Hospital
  • Leonardo Salviati, Università degli Studi di Padova
  • Dimitrios Mougiakakos, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Winfried Neuhuber, Friedrich-Alexander-Universität Erlangen-Nürnberg
  • Marco Sandri, Università degli Studi di Padova
  • Chris Meisinger, Universität Freiburg im Breisgau
  • Said Hashemolhosseini, Friedrich-Alexander-Universität Erlangen-Nürnberg
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© 2018 Taylor and Francis Group, LLC. In yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2β-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2b cKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2b cKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2b cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2b cKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22 into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22 mutant in muscle cells with ablated Csnk2b restored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior.

Citation Information
Bojana Kravic, Angelika B. Harbauer, Vanina Romanello, Luca Simeone, et al.. "In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy" Autophagy Vol. 14 Iss. 2 (2018) p. 311 - 335
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