title: Myotonic dystrophy protein kinase (DMPK) prevents ROS-induced cell death by assembling a hexokinase II-Src complex on the mitochondrial surface.
abstract: The biological functions of myotonic dystrophy protein kinase (DMPK), a serine/threonine kinase whose gene mutations cause myotonic dystrophy type 1 (DM1), remain poorly understood. Several DMPK isoforms exist, and the long ones (DMPK-A/B/C/D) are associated with the mitochondria, where they exert unknown activities. We have studied the isoform A of DMPK, which we have found to be prevalently associated to the outer mitochondrial membrane. The kinase activity of mitochondrial DMPK protects cells from oxidative stress and from the ensuing opening of the mitochondrial permeability transition pore (PTP), which would otherwise irreversibly commit cells to death. We observe that DMPK (i) increases the mitochondrial localization of hexokinase II (HK II), (ii) forms a multimeric complex with HK II and with the active form of the tyrosine kinase Src, binding its SH3 domain and (iii) it is tyrosine-phosphorylated by Src. Both interaction among these proteins and tyrosine phosphorylation of DMPK are increased under oxidative stress, and Src inhibition selectively enhances death in DMPK-expressing cells after HK II detachment from the mitochondria. Down-modulation of DMPK abolishes the appearance of muscle markers in in vitro myogenesis, which is rescued by oxidant scavenging. Our data indicate that, together with HK II and Src, mitochondrial DMPK is part of a multimolecular complex endowed with antioxidant and pro-survival properties that could be relevant during the function and differentiation of muscle fibers.
authors.affiliation: 1] CNR Institute of Neuroscience, University of Padova, Padova 35121, Italy [2] Department of Biomedical Sciences, University of Padova, Padova 35121, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Pantic
authors.forename: E
authors.initials: E
authors.lastname: Trevisan
authors.forename: A
authors.initials: A
authors.lastname: Citta
authors.forename: M P
authors.initials: MP
authors.lastname: Rigobello
authors.forename: O
authors.initials: O
authors.lastname: Marin
authors.forename: P
authors.initials: P
authors.lastname: Bernardi
authors.forename: S
authors.initials: S
authors.lastname: Salvatori
authors.forename: A
authors.initials: A
authors.lastname: Rasola
mesh_terms: D016923:Cell Death; D020868:Gene Silencing; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D065636:Myotonin-Protein Kinase; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: C585517:DMPK protein, human; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D013481:Superoxides; D006593:Hexokinase; D019061:src-Family Kinases; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases