Involvement of Mortalin in Cellular Senescence from the Perspective of its Mitochondrial Import, Chaperone, and Oxidative Stress Management Functions

Research Institute for Cell Engineering, National Institute of Advanced Industrial Science and Technology (AIST), Central 4, 1-1-1 Higashi, Tsukuba, Ibaraki 305 8562, Japan.
Annals of the New York Academy of Sciences (Impact Factor: 4.38). 05/2007; 1100(1):306-11. DOI: 10.1196/annals.1395.032
Source: PubMed


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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    • "Changes in autophagy and mitochondrial morphology are also suggested by the decrement of PARK7 and HSPA9 in the early phase. The latter is a part of the mitochondrial inner membrane transporter (TIM) complex [26] and in association with PARK7, plays "
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    Proteomics 01/2015; 15(1). DOI:10.1002/pmic.201400306 · 3.81 Impact Factor
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    • "Mortalin is essential for mitochondrial biogenesis, organellar quality control, and suppression of apoptosis (for review, see [7], [8], [34]). Mortalin variants that adversely affect mitochondrial function have been identified in PD patients, supporting the importance of Mortalin for mitochondrial function [16]. "
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    ABSTRACT: Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson's disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism.
    PLoS ONE 12/2013; 8(12):e83714. DOI:10.1371/journal.pone.0083714 · 3.23 Impact Factor
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    • "Glucoseregulated protein 75 (GRP75, also called mortalin/ mtHSP70/mot-2), a member of the cytoprotective Hsp70 family of chaperons, interacts with both PINK1 (Jin et al. 2006, 2007; Li et al. 2005; Rakovic et al. 2011) and DJ-1 (Jin et al. 2005; Li et al. 2005). GRP75 is mainly localized within the mitochondria matrix of neurons where it accomplishes several functions such as mitochondrial import and oxidative stress management (Yaguchi et al. 2007). Overexpression of GRP75 leads to extended life span in nematodes and human cells. "
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