Date Published: November 25, 2009
Publisher: Public Library of Science
Author(s): Ralph J. A. Oude Ophuis, Mietske Wijers, Miranda B. Bennink, Fons A. J. van de Loo, Jack A. M. Fransen, Bé Wieringa, Derick G. Wansink, Rafael Linden. http://doi.org/10.1371/journal.pone.0008024
Abstract: 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.
Partial Text: The myotonic dystrophy protein kinase (DMPK) gene is involved in myotonic dystrophy type I (DM1) when it is mutant and contains an unstable (CTG)n segment in its 3′ terminal exon . DMPK encodes several serine/threonine protein kinases, believed to be involved in ion homeostasis and remodeling of the actin cytoskeleton –. Up till now, emphasis in most DM1 studies was on the pathobiological significance of toxic RNA products from the mutant DMPK gene. Only relatively few studies have addressed individual protein products from the DMPK gene, including their normal structure function relationship , .
We demonstrate here that expression of MOM-anchored hDMPK A results in fragmentation of the mitochondrial network and perinuclear clustering of morphologically-altered mitochondria. In addition to these morphomechanical changes, physiological changes like loss of MMP, increased autophagosomal activity and leakage of cytochrome c accompanied by apoptosis were induced. It is difficult to bring hierarchical ordering in these events, but we propose that the fate of mitochondria in cells with hDMPK A is specified as follows: based on our observations with live-cell imaging and the finding that microtubule disruption attenuated clustering, we suppose that induction of morphological change is the initiating step that marks mitochondria for subsequent anomalous transport and clustering. Upregulation of autophagy may be an intermediate phase to rescue defective energy and clear mitochondrial waste .