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Open AccessArticle

The Charcot–Marie Tooth Disease Mutation R94Q in MFN2 Decreases ATP Production but Increases Mitochondrial Respiration under Conditions of Mild Oxidative Stress

1
Institute of Molecular Medicine, University Medical Center, Johannes Gutenberg-Universität Mainz, 55131 Mainz, Germany
2
Department of Anesthesiology, Research Center for Immunotherapy (FZI), Focus Program Translational Neurosciences (FTN), University Medical Center, Johannes Gutenberg-Universität Mainz, 55116 Mainz, Germany
3
Department of Neurology, University Hospital Düsseldorf, 40210 Düsseldorf, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(10), 1289; https://doi.org/10.3390/cells8101289
Received: 8 September 2019 / Revised: 10 October 2019 / Accepted: 14 October 2019 / Published: 21 October 2019
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. View Full-Text
Keywords: oxidative stress; MFN2; mitochondria; fusion/fission oxidative stress; MFN2; mitochondria; fusion/fission
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Wolf, C.; Zimmermann, R.; Thaher, O.; Bueno, D.; Wüllner, V.; Schäfer, M.K.; Albrecht, P.; Methner, A. The Charcot–Marie Tooth Disease Mutation R94Q in MFN2 Decreases ATP Production but Increases Mitochondrial Respiration under Conditions of Mild Oxidative Stress. Cells 2019, 8, 1289.

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