Article (Scientific journals)
Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
Burbulla, L. F.; Fitzgerald, J. C.; Stegen, K. et al.
2014In Cell Death and Disease, 5, p. 1180
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Abstract :
[en] 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Burbulla, L. F.
Fitzgerald, J. C.
Stegen, K.
Westermeier, J.
Thost, A.-K.
Kato, H.
Mokranjac, D.
Sauerwald, J.
Martins, Luisa 
Woitalla, D.
Rapaport, D.
Riess, O.
Proikas-Cezanne, T.
Rasse, T. M.
Krüger, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
More authors (5 more) Less
Language :
English
Title :
Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1.
Publication date :
2014
Journal title :
Cell Death and Disease
ISSN :
2041-4889
Publisher :
Nature Publishing Group, London, United Kingdom
Volume :
5
Pages :
e1180
Peer reviewed :
Peer Reviewed verified by ORBi
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since 02 July 2014

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