A tail-anchored myotonic dystrophy protein kinase isoform induces perinuclear clustering of mitochondria, autophagy, and apoptosis

• Published in: PloS one Vol. 4; no. 11; p. e8024
• Main Authors: Oude Ophuis, Ralph J A, Wijers, Mietske, Bennink, Miranda B, van de Loo, Fons A J, Fransen, Jack A M, Wieringa, Bé, Wansink, Derick G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.11.2009; Public Library of Science (PLoS)
• Subjects: Aberration; Adenoviruses; Animals; Apoptosis; Autophagy; Bacterial Proteins - chemistry; Biochemistry/Cell Signaling and Trafficking Structures; Biochemistry/Membrane Proteins and Energy Transduction; Biology; Cancer; Cell Biology/Cell Signaling; Cell Biology/Cellular Death and Stress Responses; Cell Biology/Cytoskeleton; Cell Biology/Membranes and Sorting; Clustering; Cytochrome; Cytochrome c; Cytochromes c - metabolism; Cytoskeleton; Deoxyribonucleic acid; DMPK protein; DNA; DNA - genetics; DNA repeat expansion; Dystrophy; E coli; Escherichia coli; Gene expression; Genes; Genetic aspects; Genetics and Genomics/Medical Genetics; Growth factors; HeLa Cells; Homeostasis; Humans; Kinases; Life sciences; Luminescent Proteins - chemistry; Membrane potential; Membrane Potentials; Mice; Microscopy; Microtubules - metabolism; Mitochondria; Mitochondria - metabolism; Mitochondrial Membranes - metabolism; Morphology; Mutation; Myotonic dystrophy; Myotonin-Protein Kinase; Neurological Disorders/Neuromuscular Diseases; Neurosciences; Patients; Phagocytosis; Physiological aspects; Protein Isoforms; Protein kinase; Protein kinases; Protein Structure, Tertiary; Protein-Serine-Threonine Kinases - chemistry; Proteins; Rheumatology; Ribonucleic acid; RNA; Tubulin; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0008024

Studies on the myotonic dystrophy protein kinase (DMPK) gene and gene products have thus far mainly concentrated on the fate of length mutation in the (CTG)n repeat at the DNA level and consequences of repeat expansion at the RNA level in DM1 patients and disease models. Surprisingly little is known about the function of DMPK protein products. We demonstrate here that transient expression of one major protein product of the human gene, the hDMPK A isoform with a long tail anchor, results in mitochondrial fragmentation and clustering in the perinuclear region. Clustering occurred in a variety of cell types and was enhanced by an intact tubulin cytoskeleton. In addition to morphomechanical changes, hDMPK A expression induces physiological changes like loss of mitochondrial membrane potential, increased autophagy activity, and leakage of cytochrome c from the mitochondrial intermembrane space accompanied by apoptosis. Truncation analysis using YFP-hDMPK A fusion constructs revealed that the protein's tail domain was necessary and sufficient to evoke mitochondrial clustering behavior. Our data suggest that the expression level of the DMPK A isoform needs to be tightly controlled in cells where the hDMPK gene is expressed. We speculate that aberrant splice isoform expression might be a codetermining factor in manifestation of specific DM1 features in patients.