Faculty Opinions recommendation of Mitochondrial fusion and function in Charcot-Marie-Tooth type 2A patient fibroblasts with mitofusin 2 mutations.

Abstract Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.

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Altered interplay between endoplasmic reticulum and mitochondria in Charcot–Marie–Tooth type 2A neuropathy

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810932116 ◽

2019 ◽

Vol 116 (6) ◽

pp. 2328-2337 ◽

Cited By ~ 22

Author(s):

Nathalie Bernard-Marissal ◽

Gerben van Hameren ◽

Manisha Juneja ◽

Christophe Pellegrino ◽

Lauri Louhivuori ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Axonal Degeneration ◽

Calcium Handling ◽

Gene Encoding ◽

Mitofusin 2 ◽

Charcot Marie Tooth ◽

Tooth Type ◽

Distal Axonal Degeneration

Mutations in theMFN2gene encoding Mitofusin 2 lead to the development of Charcot–Marie–Tooth type 2A (CMT2A), a dominant axonal form of peripheral neuropathy. Mitofusin 2 is localized at both the outer membrane of mitochondria and the endoplasmic reticulum and is particularly enriched at specialized contact regions known as mitochondria-associated membranes (MAM). We observed that expression of MFN2R94Qinduces distal axonal degeneration in the absence of overt neuronal death. The presence of mutant protein leads to reduction in endoplasmic reticulum and mitochondria contacts in CMT2A patient-derived fibroblasts, in primary neurons and in vivo, in motoneurons of a mouse model of CMT2A. These changes are concomitant with endoplasmic reticulum stress, calcium handling defects, and changes in the geometry and axonal transport of mitochondria. Importantly, pharmacological treatments reinforcing endoplasmic reticulum–mitochondria cross-talk, or reducing endoplasmic reticulum stress, restore the mitochondria morphology and prevent axonal degeneration. These results highlight defects in MAM as a cellular mechanism contributing to CMT2A pathology mediated by mutated MFN2.

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Mitochondrial Fusion Protein Mfn2 and Its Role in Heart Failure

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.681237 ◽

2021 ◽

Vol 8 ◽

Author(s):

Lei Chen ◽

Bilin Liu ◽

Yuan Qin ◽

Anqi Li ◽

Meng Gao ◽

...

Keyword(s):

Heart Failure ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Mitochondrial Fusion ◽

Mitochondrial Outer Membrane ◽

Mitochondrial Quality Control ◽

Mitofusin 2 ◽

Multifunctional Protein ◽

Pathological Conditions ◽

And Function

Mitofusin 2 (Mfn2) is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial network regulation. It is an essential multifunctional protein that participates in various biological processes under physical and pathological conditions, including mitochondrial fusion, reticulum–mitochondria contacts, mitochondrial quality control, and apoptosis. Mfn2 dysfunctions have been found to contribute to cardiovascular diseases, such as ischemia-reperfusion injury, heart failure, and dilated cardiomyopathy. Here, this review mainly focuses on what is known about the structure and function of Mfn2 and its crucial role in heart failure.

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Developmental defects and neuromuscular alterations due to mitofusin 2 gene (MFN2) silencing in zebrafish: a new model for Charcot-Marie-Tooth type 2A neuropathy

Neuromuscular Disorders ◽

10.1016/j.nmd.2010.09.002 ◽

2011 ◽

Vol 21 (1) ◽

pp. 58-67 ◽

Cited By ~ 26

Author(s):

Andrea Vettori ◽

Giorgia Bergamin ◽

Enrico Moro ◽

Giovanni Vazza ◽

Giulia Polo ◽

...

Keyword(s):

Mitofusin 2 ◽

Developmental Defects ◽

Charcot Marie Tooth ◽

New Model ◽

Tooth Type

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Charcot-Marie-Tooth polyneuropathy type 2A related to a mitofusin 2 gene mutation presenting as severe early-onset axonal polyneuropathy

Aktuelle Neurologie ◽

10.1055/s-2006-953303 ◽

2006 ◽

Vol 33 (S 1) ◽

Author(s):

C. Neusch ◽

J. Senderek ◽

M. Bähr ◽

C. Schneider-Gold

Keyword(s):

Gene Mutation ◽

Early Onset ◽

Mitofusin 2 ◽

Charcot Marie Tooth ◽

Axonal Polyneuropathy

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Faculty Opinions recommendation of Magnetic resonance neurography and diffusion tensor imaging of the peripheral nerves in patients with Charcot-Marie-Tooth Type 1A.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727611887.793566457 ◽

2019 ◽

Author(s):

Jun Li

Keyword(s):

Diffusion Tensor Imaging ◽

Magnetic Resonance ◽

Peripheral Nerves ◽

Diffusion Tensor ◽

Magnetic Resonance Neurography ◽

Charcot Marie Tooth ◽

Tooth Type ◽

And Diffusion

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The impact of symptoms on daily life as perceived by patients with Charcot-Marie-Tooth type 1A disease

Neurological Sciences ◽

10.1007/s10072-021-05254-7 ◽

2021 ◽

Author(s):

Stefano Tozza ◽

Dario Bruzzese ◽

Daniele Severi ◽

Emanuele Spina ◽

Rosa Iodice ◽

...

Keyword(s):

Quality Of Life ◽

Daily Life ◽

Short Form ◽

Lower Limbs ◽

Charcot Marie Tooth ◽

Rank Analysis ◽

Sf 36 ◽

Tooth Type ◽

The Impact

Abstract Introduction In Charcot-Marie-Tooth type 1A (CMT1A) patients, daily life is mainly influenced by mobility and ambulation dysfunctions. The aim of our work was to evaluate the perception of disturbances that mostly impact on daily life in CMT1A patients and its difference on the basis of age, gender, disability, and quality of life. Methods Forty-one CMT1A patients underwent neurological assessment focused on establishing clinical disability through the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and quality of life through the Short Form-36 (SF-36) questionnaire. We identified from CMT disturbances 5 categories [weakness in lower limbs (WLL), weakness in upper limbs (WUL), skeletal deformities (SD), sensory symptoms (SS), balance (B)] and patients classified the categories from the highest to the lowest impact on daily life (1: highest; 5: lowest). Ranking of the 5 categories, in the overall sample and in the different subgroups (dividing by gender, median of age and disease duration, CMTNS, domains of SF-36), was obtained and differences among subgroups were assessed using a bootstrap approach. Results Rank analysis showed that WLL was the most important disturbance on daily life whereas WUL had the lowest impact. In the older CMT1A group, the most important disturbance on daily life was B that was also the most relevant disturbance in patients with a greater disability. SD influenced daily life in younger patients. SS had less impact on daily life, with the exception of patients with a milder disability. Discussion Our findings demonstrated that the perception of disturbances that mostly impact on CMT1A patients’ daily life changes over the lifetime and with degree of disability.

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