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Authors: Wolf, Christina
Zimmermann, Rahel
Thaher, Osamah
Bueno, Diones
Wüllner, Verena
Schäfer, Michael
Albrecht, Philipp
Methner, Axel
Title: The Charcot-Marie tooth disease mutation R94Q in MFN2 decreases ATP production but increases mitochondrial respiration under conditions of mild oxidative stress
Online publication date: 24-Jan-2020
Year of first publication: 2019
Language: english
Abstract: Charcot–Marie tooth disease is a hereditary polyneuropathy caused by mutations in Mitofusin-2 (MFN2), a GTPase in the outer mitochondrial membrane involved in the regulation of mitochondrial fusion and bioenergetics. Autosomal-dominant inheritance of a R94Q mutation in MFN2 causes the axonal subtype 2A2A which is characterized by early onset and progressive atrophy of distal muscles caused by motoneuronal degeneration. Here, we studied mitochondrial shape, respiration, cytosolic, and mitochondrial ATP content as well as mitochondrial quality control in MFN2-deficient fibroblasts stably expressing wildtype or R94Q MFN2. Under normal culture conditions, R94Q cells had slightly more fragmented mitochondria but a similar mitochondrial oxygen consumption, membrane potential, and ATP production as wildtype cells. However, when inducing mild oxidative stress 24 h before analysis using 100 µM hydrogen peroxide, R94Q cells exhibited significantly increased respiration but decreased mitochondrial ATP production. This was accompanied by increased glucose uptake and an up-regulation of hexokinase 1 and pyruvate kinase M2, suggesting increased pyruvate shuttling into mitochondria. Interestingly, these changes coincided with decreased levels of PINK1/Parkin-mediated mitophagy in R94Q cells. We conclude that mitochondria harboring the disease-causing R94Q mutation in MFN2 are more susceptible to oxidative stress, which causes uncoupling of respiration and ATP production possibly by a less efficient mitochondrial quality control.
DDC: 610 Medizin
610 Medical sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
Place: Mainz
URN: urn:nbn:de:hebis:77-publ-595186
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: Cells
Pages or article number: Art. 1289
Publisher: MDPI
Publisher place: Basel
Issue date: 2019
ISSN: 2073-4409
Publisher URL:
Publisher DOI: 10.3390/cells8101289
Appears in collections:JGU-Publikationen

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