Yoon Sh

Formation of elongated giant mitochondria in DFO-induced cellular senescence: Involvement of enhanced fusion process through modulation of Fis1

Enlarged or giant mitochondria have often been documented in aged tissues although their role and underlying mechanism remain unclear. We report here how highly elongated giant mitochondria are formed in and related to the senescent arrest. The mitochondrial morphology was progressively changed to a highly elongated form during deferoxamine (DFO)‐induced senescent arrest of Chang cells, accompanied by increase of intracellular ROS level and decrease of mtDNA content. Interestingly, under exposure to subcytotoxic doses of H2O2 (200 µM), about 65% of Chang cells harbored elongated mitochondria with senescent phenotypes whereas ethidium bromide (EtBr) (50 ng/ml) only reformed the cristae structure. Elongated giant mitochondria were also observed in TGF β1‐ or H2O2‐induced senescent Mv1Lu cells and in old human diploid fibroblasts (HDFs). In all senescent progresses employed in this study Fis1 protein, a mitochondrial fission modulator, was commonly downexpressed. Overexpression of YFP‐Fis1 reversed both mitochondrial elongation and appearance of senescent phenotypes induced by DFO, implying its critical involvement in the arrest. Finally, we found that direct induction of mitochondrial elongation by blocking mitochondrial fission process with Fis1‐ΔTM or Drp1‐K38A was sufficient to develop senescent phenotypes with increased ROS production. These data suggest that mitochondrial elongation may play an important role as a mediator in stress‐induced premature senescence. J. Cell. Physiol. 209: 468–480, 2006.

Sterol Regulatory Element-binding Protein (SREBP)-1-mediated Lipogenesis Is Involved in Cell Senescence

Increased cell mass is one of the characteristics of senescent cells, but this event has not been clearly defined. When subcellular organellar mass was estimated with organelle-specific fluorescence dyes, we observed that most membranous organelles progressively increase in mass during cell senescence. This increase was accompanied by an increase in membrane lipids and augmented expression of lipogenic enzymes, such as fatty acid synthase (FAS), ATP citrate lyase, and acetyl-CoA carboxylase. The mature form of sterol regulatory element-binding protein (SREBP)-1 was also elevated. Increased expression of these lipogenic effectors was further observed in the liver tissues of aging Fischer 344 rats. Ectopic expression of mature form of SREBP-1 in both Chang cells and primary young human diploid fibroblasts was enough to induce senescence. Blocking lipogenesis with FAS inhibitors (cerulenin and C75) and via siRNA-mediated silencing of SREBP-1 and ATP citrate lyase significantly attenuated H2O2-induced senescence. Finally, old human diploid fibroblasts were effectively reversed to young-like cells by challenging with FAS inhibitors. Our results suggest that enhanced lipogenesis is not only a common event, but also critically involved in senescence via SREBP-1 induction, thereby contributing to the increase in organelle mass (as a part of cell mass), a novel indicator of senescence.

Roles of GSK3 in metabolic shift toward abnormal anabolism in cell senescence

Abstract  Diverse metabolic alterations, including mitochondrial dysfunction, have often been reported as characteristic phenotypes of senescent cells. However, the overall consequence of senescent metabolic features, how they develop, and how they are linked to other senescent phenotypes, such as enlarged cell volume, increased granularity, and oxidative stress, is not clear. We investigated the potential roles of glycogen synthase kinase 3 (GSK3), a multifunctional kinase, in the development of the metabolic phenotypes in cell senescence. The inactivation of GSK3 via phosphorylation is commonly observed in diverse cell senescences. Furthermore, subcytotoxic concentration of GSK3 inhibitor was sufficient to induce cellular senescence, accompanied by augmented anabolism, such as enhanced protein synthesis, and increased glycogenesis and lipogenesis, in addition to mitochondrial dysfunction. Anabolism was accomplished through glycogen synthase, eIF2B, and SREBP1. These metabolic features seem to contribute to an increase in cellular mass by increasing glycogen granules, protein mass, and organelles. Taken together, our results suggest that GSK3 is one of the key modulators of metabolic alteration, leading the cells to senescence.

Desmoplastic fibroma of the skull in an infant.

Case reportA 1-year-old girl presented with a 10-month history of progressive protuberance of the left frontal skull. Magnetic resonance imaging and computed tomography demonstrated a large osteolytic interosseous mass extending to the frontal sinus and temporal base without any intracranial invasion. A fronto-temporo-parietal craniectomy of the outer skull table and excision of an interosseous tumor resulted in local dural exposure in the temporal area that was covered by cranioplasty. Pathological examination identified desmoplastic fibroma (DF) of the skull. The patient’s cranial asymmetry was improved without recurrence of the tumor up to the 12th month after excision.DiscussionIn the literature, 11 cases of DF of the skull have been reported, two of which have involved children (one an infant). We report the second known infantile case of DF of the skull.

Risk Factors Predicting Unfavorable Neurological Outcome during the Early Period after Traumatic Brain Injury.

OBJECTIVE We aimed to identify clinico-radiological risk factors that may predict unfavorable neurological outcomes in traumatic brain injury (TBI), and to establish a guideline for patient selection in clinical trials that would improve neurological outcome during the early post TBI period. METHODS Initial clinico-radiological data of 115 TBI patients were collected prospectively. Regular neurological assessment after standard treatment divided the above patients into 2 groups after 6 months : the Favorable neurological outcome group (GOS : good & moderate disability, DRS : 0-6, LCFS : 8-10) and the Unfavorable group (GOS : severe disability-death, DRS : 7-29 and death, LCFS : 1-7 and death). RESULTS There was a higher incidence of age >/=35 years, low initial GCS score, at least unilateral pupil dilatation, and neurological deficit in the Unfavorable group. The presence of bilateral parenchymal lesions or lesions involving the midline structures in the initial brain CT was observed to be a radiological risk factor for unfavorable outcome. Multivariate analysis demonstrated that age and initial GCS score were independent risk factors. The majority of the Favorable group patients with at least one or more risk factors showed improvement of GCS scores within 2 months after TBI. CONCLUSION Patients with the above mentioned clinico-radiological risk factors who received standard treatment, but did not demonstrate neurological improvement within 2 months after TBI were deemed at risk for unfavorable outcome. These patients may be eligible candidates for clinical trials that would improve functional outcome after TBI.