the enzymatic core of the parkinson’s disease-associated protein lrrk2 impairs mitochondrial biogenesis in aging yeast

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ID: 151653
2018
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Abstract
Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson’s disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondrial biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.
Reference Key
aufschnaiter2018frontiersthe Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;Andreas Aufschnaiter;Verena Kohler;Corvin Walter;Corvin Walter;Sergi Tosal-Castano;Lukas Habernig;Heimo Wolinski;Walter Keller;F.-Nora Vögtle;Sabrina Büttner;Sabrina Büttner
Journal international journal of nanomedicine
Year 2018
DOI
10.3389/fnmol.2018.00205
URL
https://www.frontiersin.org/article/10.3389/fnmol.2018.00205/full
Keywords
mitochondria parkinson’s disease neurodegeneration neuropsychiatry biological psychiatry

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