Involvement of mortalin in cellular senescence from the perspective of its mitochondrial import, chaperone, and oxidative stress management functions.
ABSTRACT Mortalin (mtHSP70/GRP75) is a heat uninducible member of hsp70 family of proteins. Some of the established features of mortalin include its various subcellular sites, multiple binding partners, and differential subcellular distribution in normal and immortal cells. Overexpression of mortalin leads to extended life span in nematode and normal human cells. On the other hand, it serves as a major target for oxidation and was shown to be involved in old age pathologies including Parkinson's and Alzheimer's disease. Since mortalin interacts with many proteins, its modifications in response to stress and damage caused by intracellular oxidation are likely to generate pleiotropic effects. For example, (a) inefficient import of mitochondrial proteins by mortalin-Tim complexes may result into inefficient mitochondrial genesis, energy generation, and functional decline and (b) inefficient chaperoning of proteins can result into a garbage catastrophe.
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ABSTRACT: Telomerase inhibition causes progressive telomere shortening and cellular senescence, which constitutes a universal barrier to tumor growth and therefore an attractive target for tumor therapy. To expanded our previous studies we investigated the global effects of telomere dysfunction on the proteome of tumor cells in order to find novel senescence biomarkers. Telomerase-deficient HCT-116 cell clones were analyzed by a quantitative proteomic approach using isotope-coded protein labeling (ICPL) and nanoflow-HPLC-MS/MS. Stringent reduction of the extensive proteomic data from this tumor cell model revealed a list of 59 markers including proteins identified in our former studies and a number of novel proteins involved in tumorigenesis and metastasis such as SFN, S100A4, ANXA2, and LGALS1. A loss of the chromatin protein HMGB2 was demonstrated not only in various telomerase-inhibited clones of different tumor cell lines, but also normal human fibroblasts undergoing replicative senescence, and in aging telomerase knockout mice. Impressively, a coherent and dense network of protein-protein interactions for the bulk of the markers was revealed and their implementation in signaling pathways involving key regulators for tumorigenesis. These results have an impact for the understanding of telomere- and senescence-related signal transduction in tumor cells in consideration of the general lack of senescence markers. Induction of cellular senescence constitutes a potent concept for tumor therapy which interferes with immortalization and additional hallmarks of cancer. The application of a powerful quantitative proteomic approach using isotope-coded protein labeling to an approved model for senescence represented by telomerase inhibited tumor cells led to the identification of novel candidate biomarkers for telomere dysfunction and replicative senescence. Thereby, the identified markers not only fit in the context of the investigated processes with a relevance for additional hallmarks of cancer but are also involved in a strong interaction network and integrated in canonical pathways centered around key cancer-relevant proteins. These potential markers alone or in combination will significantly extend the view on telomere-associated signal transduction in tumor cells and contribute to the field of cellular senescence and aging in consideration of the general lack of biomarkers in this regard.Journal of proteomics 08/2013; · 5.07 Impact Factor
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ABSTRACT: Resveratrol (RESV), a polyphenolic natural compound, has long been acknowledged to have cardioprotective and antiinflammatory actions. Evidence suggests that RESV has antioxidant properties that reduce the formation of reactive oxygen species leading to oxidative stress and apoptotic death of dopaminergic (DAergic) neurons in Parkinson's disease (PD). Recent literature has recognized hyperglycemia as a cause of oxidative stress reported to be harmful for the nervous system. In this context, our study aimed (a) to evaluate the effect of RESV against high glucose (HG)-induced oxidative stress in DAergic neurons, (b) to study the antiapoptotic properties of RESV in HG condition, and c) to analyze RESV's ability to modulate p53 and GRP75, a p53 inactivator found to be under expressed in postmortem PD brains. Our results suggest that RESV protects DAergic neurons against HG-induced oxidative stress by diminishing cellular levels of superoxide anion. Moreover, RESV significantly reduces HG-induced apoptosis in DAergic cells by modulating DNA fragmentation and the expression of several genes implicated in the apoptotic cascade, such as Bax, Bcl-2, cleaved caspase-3, and cleaved PARP-1. RESV also prevents the pro-apoptotic increase of p53 in the nucleus induced by HG. Such data strengthens the correlation between hyperglycemia and neurodegeneration, while providing new insight on the high occurrence of PD in patients with diabetes. This study enlightens potent neuroprotective roles for RESV that should be considered as a nutritional recommendation for preventive and/or complementary therapies in controlling neurodegenerative complications in diabetes.Neurotoxicity Research 11/2013; · 2.87 Impact Factor
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ABSTRACT: The mitochondrial chaperone mortalin was implicated in Parkinson's disease (PD) because of its reduced levels in the brains of PD patients and disease-associated rare genetic variants that failed to rescue impaired mitochondrial integrity in cellular knockdown models. To uncover the molecular mechanisms underlying mortalin-related neurodegeneration, we dissected the cellular surveillance mechanisms related to mitochondrial quality control, defined the effects of reduced mortalin function at the molecular and cellular levels and investigated the functional interaction of mortalin with Parkin and PINK1, two PD-related proteins involved in mitochondrial homeostasis. We found that reduced mortalin function leads to: (1) activation of the mitochondrial unfolded protein response (UPR(mt)), (2) increased susceptibility towards intramitochondrial proteolytic stress, (3) increased autophagic degradation of fragmented mitochondria and (4) reduced mitochondrial mass in human cells in vitro and ex vivo. These alterations caused increased vulnerability toward apoptotic cell death. Proteotoxic perturbations induced by either partial loss of mortalin or chemical induction were rescued by complementation with native mortalin, but not disease-associated mortalin variants, and were independent of the integrity of autophagic pathways. However, Parkin and PINK1 rescued loss of mortalin phenotypes via increased lysosomal-mediated mitochondrial clearance and required intact autophagic machinery. Our results on loss of mortalin function reveal a direct link between impaired mitochondrial proteostasis, UPR(mt) and PD and show that effective removal of dysfunctional mitochondria via either genetic (PINK1 and Parkin overexpression) or pharmacological intervention (rapamycin) may compensate mitochondrial phenotypes.Cell Death & Disease 01/2014; 5:e1180. · 6.04 Impact Factor