Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1

Guido Krebiehl*, Sabine Ruckerbauer, Lena F. Burbulla, Nicole Kieper, Brigitte Maurer, Jens Waak, Hartwig Wolburg, Zemfira Gizatullina, Frank N. Gellerich, Dirk Woitalla, Olaf Riess, Philipp J. Kahle, Tassula Proikas-Cezanne, Rejko Krüger

*Corresponding author for this work

Research output: Contribution to journalArticle

241 Scopus citations

Abstract

Background: Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined. Methodology/Principal Findings: Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2. Conclusions/Significance: We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease.

Original languageEnglish (US)
Article numbere9367
JournalPloS one
Volume5
Issue number2
DOIs
StatePublished - Feb 23 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Krebiehl, G., Ruckerbauer, S., Burbulla, L. F., Kieper, N., Maurer, B., Waak, J., Wolburg, H., Gizatullina, Z., Gellerich, F. N., Woitalla, D., Riess, O., Kahle, P. J., Proikas-Cezanne, T., & Krüger, R. (2010). Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1. PloS one, 5(2), [e9367]. https://doi.org/10.1371/journal.pone.0009367