DMPK prevents ROS-induced cell death by assembling a HK II-Src complex on mitochondrial surface
Year: 2012
Type: dissertation
Abstract: DMPK is a serine/threonine protein kinase that was initially proposed to be the cause of the most frequent adult muscular dystrophy, myotonic dystrophy 1 (DM1). Recently, it has been shown that DMPK is not the primary determinant of the DM1, but its deletion causes late onset myopathy and cardiac abnormalities in knock-out mice. Evidence present in the literature suggests a mitochondrial localization of high MW DMPK isoforms in muscle and cardiac tissue. However, to date, there is not a single association of mitochondria-anchored isoforms with the respective function of the organelle in the affected tissues. Therefore, we have examined the role of mitochondria-anchored isoform A, either by stably expressing it in cells lacking endogenous protein, or by stably silencing the endogenous one. DMPK significantly decreased levels of mitochondrial superoxide and consequently increased cell survival in prolonged serum and glucose depletion, both in SAOS-2 and rhabdomyosarcoma cells. At the molecular level we have found DMPK to interact with HK II and Src, increasing the HK II association to mitochondria. Detachment of HK II from mitochondria abolished differences in superoxide levels, while a HK II inhibitor 5-TG protected cells from death by stabilizing HK II on the OMM and by decreasing mitochondrial ROS in the absence of DMPK. Src activity was also important for HK II maintenance on OMM since its inhibition sensitized only DMPK-expressing cells to detachment of HK II. These data attribute an antiapoptotic role to DMPK due to an unprecedented link to HK II and its protective effect against mitochondrial ROS.
Author: Boris Pantic
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2280115086