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

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

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Frontiers in molecular neuroscience. - 11 (2018) , 00205, ISSN: 1662-5099

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2019
Urheber
Aufschnaiter, Andreas
Kohler, Verena
Walter, Corvin
Tosal-Castano, Sergi
Habernig, Lukas
Wolinski, Heimo
Keller, Walter
Vögtle, Friederike-Nora
Büttner, Sabrina

DOI
10.3389/fnmol.2018.00205
URN
urn:nbn:de:bsz:25-freidok-1487308
Rechteinformation
Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
25.03.2025, 13:44 MEZ

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  • 2019

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