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The enzymatic core of the Parkinson’s disease-associated protein LRRK2 impairs mitochondrial biogenesis in aging yeast
Institute of Molecular Biosciences, University of Graz, Graz, Austria.ORCID iD: 0000-0001-6571-2162
Institute of Molecular Biosciences, University of Graz, Graz, Austria.ORCID iD: 0000-0002-1241-162X
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
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2018 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 205Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2018. Vol. 11, article id 205
Keywords [en]
LRRK2, Parkinson’s disease, neurodegeneration, mitochondria, complex IV, cell death, yeast, aging
National Category
Biochemistry and Molecular Biology Neurology
Identifiers
URN: urn:nbn:se:umu:diva-215038DOI: 10.3389/fnmol.2018.00205ISI: 000435852400001PubMedID: 29977190Scopus ID: 2-s2.0-85049048631OAI: oai:DiVA.org:umu-215038DiVA, id: diva2:1802941
Funder
Swedish Research Council, 2015-05468Åke Wiberg Foundation, M16-0130Carl Tryggers foundation , CTS16:85German Research Foundation (DFG), RTG 2202German Research Foundation (DFG), Emmy Noether ProgrammeAvailable from: 2023-10-06 Created: 2023-10-06 Last updated: 2023-10-16Bibliographically approved

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Kohler, AndreasKohler, Verena

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