The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

Pich, Sara; Bach, Daniel; Briones, Paz; Liesa, Marc; Camps, Marta; Testar, Xavier; Palacín, Manuel; Zorzano, Antonio

doi:10.1093/hmg/ddi149

Cited by 455Mitochondrial Function and PathologyHereditary Neurological DisordersAutophagy in Disease and Therapy

The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

Pich, Sara, Bach, Daniel, Briones, Paz, Liesa, Marc, Camps, Marta, Testar, Xavier, Palacín, Manuel, Zorzano, Antonio·2005·Human Molecular Genetics

DOI 10.1093/hmg/ddi149

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Abstract

Mitofusin-2 (Mfn2) is a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells and mutations in the Mfn2 gene cause Charcot-Marie-Tooth neuropathy type 2A. Here, we show that Mfn2 loss-of-function inhibits pyruvate, glucose and fatty acid oxidation and reduces mitochondrial membrane potential, whereas Mfn2 gain-of-function increases glucose oxidation and mitochondrial membrane potential. As to the mechanisms involved, we have found that Mfn2 loss-of-function represses nuclear-encoded subunits of OXPHOS complexes I, II, III and V, whereas Mfn2 overexpression induced the subunits of complexes I, IV and V. Obesity-induced Mfn2 deficiency in rat skeletal muscle was also associated with a decrease in the subunits of complexes I, II, III and V. In addition, the effect of Mfn2 overexpression on mitochondrial metabolism was mimicked by a truncated Mfn2 mutant that is inactive as a mitochondrial fusion protein. Our results indicate that Mfn2 triggers mitochondrial energization, at least in part, by regulating OXPHOS expression through signals that are independent of its role as a mitochondrial fusion protein.

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Lower levels of Mfn2 have been associated with fragmentation of the mitochondrial network and decrease of membrane potential in rat skeletal muscle.
“Lower levels of Mfn2 have been associated with the fragmentation of the mitochondrial network and the decrease of membrane potential in rat skeletal muscle (Pich et al., 2005).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Pich et al., 2005

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Authors: Pich, S., Bach, D., Briones, P., Liesa, M., Camps, M., Testar, X., Palacín, M., & Zorzano, A.
Affiliations: Parc Científic de Barcelona (ES)
Corresponding author: Pich, Sara
ORCID: Liesa, Marc
Camps, Marta
Testar, Xavier
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2005-04-13
Volume: 14
Issue: 11
Pages: 1405-1415
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddi149
OpenAlex: W2137580945
Cited by: 455
References: 83
Citations by year: 2026: 6 · 2025: 13 · 2024: 12 · 2023: 29 · 2022: 26 · 2021: 23 · 2020: 24 · 2019: 16 · 2018: 27 · 2017: 25 · 2016: 14 · 2015: 23 · 2014: 29 · 2013: 34 · 2012: 35
FWCI: 5.79
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: Generalitat de Catalunya
Ministerio de Ciencia y Tecnología
Instituto de Salud Carlos III
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: mitofusin 2, Charcot-Marie-Tooth disease type 2A, oxidative phosphorylation, mitochondrial membrane potential, mitochondrial fusion, mitochondrial bioenergetics, glucose oxidation, fatty acid oxidation, pyruvate oxidation, obesity, skeletal muscle, mitochondrial dysfunction
MeSH terms: Base Sequence, Charcot-Marie-Tooth Disease, Fatty Acids, Glucose, Humans, Membrane Potentials, Membrane Proteins, Mitochondria, Oxidation-Reduction, Oxidative Phosphorylation, DNA Primers, Pyruvic Acid, GTP Phosphohydrolases, Mitochondrial Proteins

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The Charcot-Marie-Tooth type 2A gene product, Mfn2, up-regulates fuel oxidation through expression of OXPHOS system

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