Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1

L. F. Burbulla, J. C. Fitzgerald, K. Stegen, J. Westermeier, A. K. Thost, H. Kato, D. Mokranjac, J. Sauerwald, L. M. Martins, D. Woitalla, D. Rapaport, O. Riess, T. Proikas-Cezanne, T. M. Rasse, R. Krüger

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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.

Original languageEnglish
Article numbere1180
JournalCell Death and Disease
Volume5
Issue number4
DOIs
Publication statusPublished - Apr 2014

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Parkinson Disease
Mitochondria
mortalin
Phenotype
Unfolded Protein Response
Mitochondrial Proteins
Brain Diseases
Sirolimus
Rare Diseases
Quality Control
Homeostasis
Cell Death
Pharmacology
Proteins

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Burbulla, L. F., Fitzgerald, J. C., Stegen, K., Westermeier, J., Thost, A. K., Kato, H., ... Krüger, R. (2014). Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1. Cell Death and Disease, 5(4), [e1180]. https://doi.org/10.1038/cddis.2014.103

Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1. / Burbulla, L. F.; Fitzgerald, J. C.; Stegen, K.; Westermeier, J.; Thost, A. K.; Kato, H.; Mokranjac, D.; Sauerwald, J.; Martins, L. M.; Woitalla, D.; Rapaport, D.; Riess, O.; Proikas-Cezanne, T.; Rasse, T. M.; Krüger, R.

In: Cell Death and Disease, Vol. 5, No. 4, e1180, 04.2014.

Research output: Contribution to journalArticle

Burbulla, LF, Fitzgerald, JC, Stegen, K, Westermeier, J, Thost, AK, Kato, H, Mokranjac, D, Sauerwald, J, Martins, LM, Woitalla, D, Rapaport, D, Riess, O, Proikas-Cezanne, T, Rasse, TM & Krüger, R 2014, 'Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1', Cell Death and Disease, vol. 5, no. 4, e1180. https://doi.org/10.1038/cddis.2014.103
Burbulla, L. F. ; Fitzgerald, J. C. ; Stegen, K. ; Westermeier, J. ; Thost, A. K. ; Kato, H. ; Mokranjac, D. ; Sauerwald, J. ; Martins, L. M. ; Woitalla, D. ; Rapaport, D. ; Riess, O. ; Proikas-Cezanne, T. ; Rasse, T. M. ; Krüger, R. / Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1. In: Cell Death and Disease. 2014 ; Vol. 5, No. 4.
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