A subcellular analysis of genetic modulation of PINK1 on mitochondrial alterations, autophagy and cell death

P. Lenzi, R. Marongiu, A. Falleni, V. Gelmetti, C. L. Busceti, S. Michiorri, E. M. Valente, F. Fornai

Research output: Contribution to journalArticle

Abstract

Mutations in the PTEN-induced putative kinase1 (PINK1) represent the second most frequent cause of autosomal recessive Parkinson's disease. The PINK1 protein mainly localizes to mitochondria and interacts with a variety of proteins, including the pro-autophagy protein beclin1 and the ubiquitin-ligase parkin. Upon stress conditions, PINK1 is known to recruit parkin at the surface of dysfunctional mitochondria and to activate the mitophagy cascade. Aim of this study was to use a simple and highly reproducible catecholamine cell model and transmission electron microscopy to characterize whether PINK1 could affect mitochondrial homeostasis, the recruitment of specific proteins at mitochondria, mitophagy and apoptosis. Samples were analyzed both in baseline conditions and following treatment with methamphetamine (METH), a neurotoxic compound which strongly activates autophagy and produces mitochondrial damage. Our data provide robust sub-cellular evidence that the modulation of PINK1 levels dramatically affects the morphology and number of mitochondria and the amount of cell death. In particular, especially upon METH exposure, PINK1 is able to increase the total number of mitochondria, concurrently recruit beclin1, parkin and ubiquitin and enhance the clearance of damaged mitochondria. In the absence of functional PINK1 and upon autophagy stress, we observe a failure of the autophagy system at large, with marked accumulation of dysfunctional mitochondria and dramatic increase of apoptotic cell death. These findings highlight the strong neuroprotective role of PINK1 as a key protein in the surveillance and regulation of mitochondrial homeostasis.

Original languageEnglish
Pages (from-to)194-217
Number of pages24
JournalArchives Italiennes de Biologie
Volume150
Issue number2-3
Publication statusPublished - 2012

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Keywords

  • Beclin1
  • Methamphetamine
  • Mitophagy
  • Parkin
  • Parkinson's disease

ASJC Scopus subject areas

  • Medicine(all)
  • Cell Biology
  • Physiology

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