Mitofusin gain and loss of function drive pathogenesis in
            <i>Drosophila</i>
            models of
            <scp>CMT</scp>
            2A neuropathy

Fissi, Najla El; Rojo, Manuel; Aouane, Aїcha; Karataş, Esra; Poliacikova, Gabriela; David, Claudine; Royet, Julien; Rival, Thomas

doi:10.15252/embr.202050703

Cited by 20 publications

(26 citation statements)

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“…Regardless of the precise molecular mechanism, mitochondrial aggregation accompanied by decreased mitochondrial fusion and axonal transport/localization likely drives axonal degeneration in Thy1.2-MFN2 R94Q -expressing mice, as numerous prior in vitro studies support that degeneration results from local axonal energy failure due to abnormal mitochondrial function, interaction with other organelles, including ER and lysosomes, and improper localization to sites of energy demand (2,6,26,27,52,56). Of note, a recent study showed that the MFN2 R94Q mutant in flies led to similar cytoplasmic aggregates of unfused mitochondria and axonal pathology, supporting the dominant negative tethering model for the action of this and other GTPase domain mutants (57). Interestingly, the authors found that 2 other mutants (L76P and R364W) showed evidence of enhanced fusion, but surprisingly, still caused mitochondrial dysfunction and altered axonal mitochondrial localization.…”

Section: Discussionmentioning

confidence: 57%

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model

Zhou¹,

Carmona

Muhammad³

et al. 2019

Journal of Clinical Investigation

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Figure 1. Impaired growth rate, sensorimotor function, grip strength, and vision in Thy1.2-MFN2 R94Q transgenic mice. (A) Schematic of the Thy1.2-MFN2 R94Q transgenic construct. The expression of human MFN2 R94Q or control MFN2 WT (N terminus tagged with Flag) was driven by the neuron-specific mouse Thy1.2 promoter. (B) Representative image of a nontransgenic (nTg) mouse, a Thy1.2-MFN2 WT mouse, and a Thy1.2-MFN2 R94Q mouse (5 months old). (C) Immunoblot of Flag-MFN2 WT or Flag-MFN2 R94Q transgene expression (14-month-old mice). Red arrow, Flag-MFN2; black arrow, endogenous mouse Mfn2. Expression levels of MFN2 WT or MFN2 R94Q transgenes were identical and slightly below endogenous Mfn2 levels. n = 3 mice/genotype. (D) Immunostaining of Flag-MFN2 WT or Flag-MFN2 R94Q protein expression and localization. Mouse cortex or spinal cord (5-month-old mice). Anti-Flag (red) and DAPI (blue). Scale bars: 50 μM. Punctate mitochondrial staining was observed in both transgenic lines, but only MFN2 R94Q mice showed mitochondrial accumulations in neuronal cytoplasm and proximal axons. n = 3 mice/genotype. (E) Body weight. Data are represented as mean ± SEM. n = 6-52 per genotype per time point. Student's 2-tailed t test (nTg vs. MFN2 R94Q). *P < 0.05. (F) Survival curve. nTg (n = 59), MFN2 WT (n = 29), MFN2 R94Q (n = 124). log-rank test with Bonferroni's correction. nTg vs. MFN2 WT , P > 0.05, not significant. nTg vs. MFN2 R94Q , P < 0.01. MFN2 WT vs. MFN2 R94Q , P < 0.05. (G) Open-field test (total activity) and (H) open-field test (rearing). Total activity was not significantly different between groups. nTg (n = 5), MFN2 WT (n = 5), MFN2 R94Q (n = 6) (3-month-old mice). (I) Rotarod testing. nTg (n = 5), MFN2 WT (n = 5), MFN2 R94Q (n = 6). (J) Grip-strength testing (forelimbs). nTg (n = 8-11), MFN2 WT (n = 5), MFN2 R94Q (n = 6). (K) Visual acuity measured by OKR. nTg (n = 6), MFN2 WT (n = 3), MFN2 R94Q (n = 7). In G-K, data are represented as mean ± SEM. Two-way ANOVA with Tukey's test was used for multiple comparison.

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Section: Discussionmentioning

confidence: 57%

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model

Zhou¹,

Carmona

Muhammad³

et al. 2019

Journal of Clinical Investigation

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“…With respect to CMT2A2, the consequences of its mutations on MFN2 activity and neuronal function were recently investigated in a Drosophila fly model (96). Analysis of four pathological mutations (R94Q, R364W, T105M, and L76P) revealed that they all increased mtDNA mutations, decreased oxidative metabolism, and induced mitochondrial depletion at neuromuscular junctions.…”

Section: B Patients Carrying Mutations In Mitochondrial Fission and mentioning

confidence: 99%

“…Remarkably, R364W and L76P mutations stimulated mitochondrial fusion. It was proposed that both excessive mitochondrial aggregation and fusion can underlie CMT2A pathophysiology (96). Changes in mitochondrial (ultra)structure and mitochondrial function have also been described in human aging (356)…”

Section: B Patients Carrying Mutations In Mitochondrial Fission and mentioning

confidence: 99%

Mitochondrial Morphofunction in Mammalian Cells

Bulthuis

Adjobo‐Hermans

Willems

et al. 2019

Antioxidants & Redox Signaling

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Significance: In addition to their classical role in cellular ATP production, mitochondria are of key relevance in various (patho)physiological mechanisms including second messenger signaling, neuro-transduction, immune responses and death induction. Recent Advances: Within cells, mitochondria are motile and display temporal changes in internal and external structure (''mitochondrial dynamics''). During the last decade, substantial empirical and in silico evidence was presented demonstrating that mitochondrial dynamics impacts on mitochondrial function and vice versa. Critical Issues: However, a comprehensive and quantitative understanding of the bidirectional links between mitochondrial external shape, internal structure and function (''morphofunction'') is still lacking. The latter particularly hampers our understanding of the functional properties and behavior of individual mitochondrial within single living cells. Future Directions: In this review we discuss the concept of mitochondrial morphofunction in mammalian cells, primarily using experimental evidence obtained within the last decade. The topic is introduced by briefly presenting the central role of mitochondria in cell physiology and the importance of the mitochondrial electron transport chain (ETC) therein. Next, we summarize in detail how mitochondrial (ultra)structure is controlled and discuss empirical evidence regarding the equivalence of mitochondrial (ultra)structure and function. Finally, we provide a brief summary of how mitochondrial morphofunction can be quantified at the level of single cells and mitochondria, how mitochondrial ultrastructure/volume impacts on mitochondrial bioreactions and intramitochondrial protein diffusion, and how mitochondrial morphofunction can be targeted by small molecules.

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“…While a few of the CMT2A MFN2 variants studied appear to be fusion incompetent, (5,52,62), there are other CMT2A MFN2 variants that do not seem to affect mitochondrial morphology (40,63). Conversely, some CMT2A MFN2 variants actually enhance fusion (38,39). Thus, impaired mitochondrial fusion does not appear to be necessary to cause CMT2A.…”

Section: Discussionmentioning

confidence: 91%

“…However, despite the general assumption that impaired mitochondrial fusion causes the peripheral neuropathy phenotype, only a few pathogenic MFN2 variants have been investigated functionally for their effects on MFN2 functions. While some pathogenic MFN2 variants do impair fusion (36,37), unexpectedly, other pathogenic variants seem to increase fusion (38,39), while several pathogenic variants do not appear to affect fusion at all (37,40,41). These findings raise the possibility that impaired fusion does not lead to peripheral neuropathy per se.…”

Section: Introductionmentioning

confidence: 87%

Characterization of a novel variant in the HR1 domain ofMFN2in a patient with ataxia, optic atrophy and sensorineural hearing loss

Sharma

Saubouny

Joel

et al. 2021

Preprint

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Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

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Mitofusin gain and loss of function drive pathogenesis in Drosophila models of CMT 2A neuropathy

Cited by 20 publications

References 0 publications

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model

Restoring mitofusin balance prevents axonal degeneration in a Charcot-Marie-Tooth type 2A model

Mitochondrial Morphofunction in Mammalian Cells

Characterization of a novel variant in the HR1 domain ofMFN2in a patient with ataxia, optic atrophy and sensorineural hearing loss

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