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The enzymatic core of the Parkinson’s disease-associated protein LRRK2 impairs mitochondrial biogenesis in aging yeast

Kohler, Andreas, Dr. rer. nat. 1988- (author)
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Kohler, Verena, 1992- (author)
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Walter, Corvin (author)
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
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Tosal-Castano, Sergi (author)
Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
Habernig, Lukas (author)
Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
Wolinski, Heimo (author)
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Keller, Walter (author)
Institute of Molecular Biosciences, University of Graz, Graz, Austria
Vögtle, F.-Nora (author)
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany
Büttner, Sabrina (author)
Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut,University of Graz, Austria
Aufschnaiter, Andreas (author)
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 (creator_code:org_t)
2018-06-21
2018
English.
In: Frontiers in Molecular Neuroscience. - : Frontiers Media S.A.. - 1662-5099. ; 11
  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)
NATURVETENSKAP  -- Biologi (hsv//swe)
NATURAL SCIENCES  -- Biological Sciences (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

LRRK2
Parkinson’s disease
neurodegeneration
mitochondria
complex IV
cell death
yeast
aging

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