10.6084/m9.figshare.5624836.v1
Bojana Kravic
Bojana
Kravic
Angelika B. Harbauer
Angelika B.
Harbauer
Vanina Romanello
Vanina
Romanello
Luca Simeone
Luca
Simeone
F.-Nora Vögtle
F.-Nora
Vögtle
Tobias Kaiser
Tobias
Kaiser
Marion Straubinger
Marion
Straubinger
Danyil Huraskin
Danyil
Huraskin
Martin Böttcher
Martin
Böttcher
Cristina Cerqua
Cristina
Cerqua
Eva Denise Martin
Eva Denise
Martin
Daniel Poveda-Huertes
Daniel
Poveda-Huertes
Andreas Buttgereit
Andreas
Buttgereit
Adam J. Rabalski
Adam J.
Rabalski
Dieter Heuss
Dieter
Heuss
Rüdiger Rudolf
Rüdiger
Rudolf
Oliver Friedrich
Oliver
Friedrich
David Litchfield
David
Litchfield
Michael Marber
Michael
Marber
Leonardo Salviati
Leonardo
Salviati
Dimitrios Mougiakakos
Dimitrios
Mougiakakos
Winfried Neuhuber
Winfried
Neuhuber
Marco Sandri
Marco
Sandri
Chris Meisinger
Chris
Meisinger
Said Hashemolhosseini
Said
Hashemolhosseini
In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy
Taylor & Francis Group
2017
CSNK2/CK2
CSNK2B
homeostasis
mitochondria
mitophagy
p62
PINK1
skeletal myopathy
TOMM22
2017-11-22 11:41:36
Dataset
https://tandf.figshare.com/articles/dataset/In_mammalian_skeletal_muscle_phosphorylation_of_TOMM22_by_protein_kinase_CSNK2_CK2_controls_mitophagy/5624836
<p>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 <i>Csnk2b</i>/<i>Ck2β</i>-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle <i>Csnk2b</i> 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 <i>Csnk2b</i> 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 <i>in vitro</i> using mitochondria isolated from muscles of skeletal muscle <i>Csnk2b</i> cKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle <i>Csnk2b</i> 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 <i>in vivo</i> electroporation of phosphomimetic <i>Tomm22</i> into muscles of mice. Importantly, transfection of the phosphomimetic <i>Tomm22</i> mutant in muscle cells with ablated <i>Csnk2b</i> 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.</p>