Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Franco, Antonietta; Dang, Xiawei; Walton, Emily K.; Ho, Joshua N.; Zabłocka, Barbara; Ly, Cindy V.; Miller, Timothy M.; Baloh, Robert H.; Shy, Michael E.; Yoo, Andrew S.; Dorn, Gerald W.

doi:10.7554/elife.61119

Cited by 41 publications

(92 citation statements)

References 47 publications

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“…MFN2 plays an essential role in mitochondrial fusion ( Chen et al, 2003 ), endoplasmic reticulum-mitochondria tethering ( Filadi et al, 2015 ; Larrea et al, 2019 ), and reactive oxygen species (ROS) production ( Pich et al, 2005 ; van Hameren et al, 2019 ). Proper mitochondrial morphology and positioning allows for local metabolic and energetic needs within axons to be met, which is critical to properly regulate the formation of neuromuscular junctions ( Franco et al, 2020 ). MFN2, located in the mitochondrial outer membrane, regulates mitochondrial fusion to maintain mitochondrial morphology by balancing the process of mitochondrial fission.…”

Section: Discussionmentioning

confidence: 99%

MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons

Mou

Dein

Chen

et al. 2021

Front. Mol. Neurosci.

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Charcot-Marie-Tooth (CMT) disease is one of the most common genetically inherited neurological disorders and CMT type 2A (CMT 2A) is caused by dominant mutations in the mitofusin-2 (MFN2) gene. MFN2 is located in the outer mitochondrial membrane and is a mediator of mitochondrial fusion, with an essential role in maintaining normal neuronal functions. Although loss of MFN2 induces axonal neuropathy, the detailed mechanism by which MFN2 deficiency results in axonal degeneration of human spinal motor neurons remains largely unknown. In this study, we generated MFN2-knockdown human embryonic stem cell (hESC) lines using lentivirus expressing MFN2 short hairpin RNA (shRNA). Using these hESC lines, we found that MFN2 loss did not affect spinal motor neuron differentiation from hESCs but resulted in mitochondrial fragmentation and dysfunction as determined by live-cell imaging. Notably, MFN2-knockodwn spinal motor neurons exhibited CMT2A disease-related phenotypes, including extensive perikaryal inclusions of phosphorylated neurofilament heavy chain (pNfH), frequent axonal swellings, and increased pNfH levels in long-term cultures. Importantly, MFN2 deficit impaired anterograde and retrograde mitochondrial transport within axons, and reduced the mRNA and protein levels of kinesin and dynein, indicating the interfered motor protein expression induced by MFN2 deficiency. Our results reveal that MFN2 knockdown induced axonal degeneration of spinal motor neurons and defects in mitochondrial morphology and function. The impaired mitochondrial transport in MFN2-knockdown spinal motor neurons is mediated, at least partially, by the altered motor proteins, providing potential therapeutic targets for rescuing axonal degeneration of spinal motor neurons in CMT2A disease.

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Section: Discussionmentioning

confidence: 99%

MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons

Mou

Dein

Chen

et al. 2021

Front. Mol. Neurosci.

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“…Given the multifaceted roles of MFN2 and above-mentioned broad clinical variability, it is also possible that a combination of functions contributes to pathology. Excitingly, small molecules designed to activate MFN2, which restore mitochondrial morphology and motility, have recently been shown to overcome CMT2A mutants in reprogrammed patient motor neurons and in a mouse model [ 112 , 113 ]. While it remains to be determined how this molecule affects other MFN2 functions, it certainly offers a promising therapeutic option.…”

Section: Pathogenic Variants In Proteins Mediating Mitochondrial Dynamics That Cause Peripheral Neuropathymentioning

confidence: 99%

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Sharma

Pfeffer

Shutt

2021

Biology

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Mitochondria are dynamic organelles capable of fusing, dividing, and moving about the cell. These properties are especially important in neurons, which in addition to high energy demand, have unique morphological properties with long axons. Notably, mitochondrial dysfunction causes a variety of neurological disorders including peripheral neuropathy, which is linked to impaired mitochondrial dynamics. Nonetheless, exactly why peripheral neurons are especially sensitive to impaired mitochondrial dynamics remains somewhat enigmatic. Although the prevailing view is that longer peripheral nerves are more sensitive to the loss of mitochondrial motility, this explanation is insufficient. Here, we review pathogenic variants in proteins mediating mitochondrial fusion, fission and transport that cause peripheral neuropathy. In addition to highlighting other dynamic processes that are impacted in peripheral neuropathies, we focus on impaired mitochondrial quality control as a potential unifying theme for why mitochondrial dysfunction and impairments in mitochondrial dynamics in particular cause peripheral neuropathy.

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“…CMT2A also manifests significant mitochondrial fragmentation and axonal transport defects 16,17,19,91 . Targeting mitochondrial fragmentation provides a promising therapeutic strategy for treating CMT2 diseases as demonstrated elegantly by a recent study 18 . Intermittent activation of endogenous mitofusin with a small molecule normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses 18 .…”

Section: Discussionmentioning

confidence: 98%

“…Neuronal cells are characterized by a complex morphology and functional sophistication linked to the remarkable length of their processes and to the requirement of rapid metabolic changes. These cells are particularly dependent on mitochondrial functions, on fission/fusion equilibrium and on mitochondrial localization [16][17][18][19][20][21][22] . Although the rules governing these changes and their functional significance are not fully understood, dysfunction of mitochondrial dynamics has been identified as a pathogenetic factor for disorders of both the central and the peripheral nervous systems 23 .…”

Section: Introductionmentioning

confidence: 99%

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

Guerra

et al. 2021

Preprint

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Recent evidence has uncovered an important role of Rab7 in regulating mitochondrial morphology and function. Missense mutation(s) of Rab7 underlies the pathogenesis of Charcot Marie Tooth 2B (CMT2B) peripheral neuropathy. Herein, we investigated how mitochondrial morphology and function were impacted by the CMT2B associated Rab7V162M mutation in fibroblasts from human CMT2B patients as well as in a knockin mouse model. In contrast to recently published results from studies of using heterologous overexpression systems, our results have demonstrated significant mitochondrial fragmentation in fibroblasts of both human CMT2B patients and CMT2B mouse embryonic fibroblasts (MEFs). Furthermore, we have shown that mitochondria were fragmented and axonal mitochondrial movement was dysregulated in primary cultured E18 dorsal root ganglion (DRG) sensory neurons, but not in E18 hippocampal and cortical primary neurons. We also show that inhibitors to either the mitochondrial fission protein Drp1 or to the nucleotide binding to Rab7 normalized the mitochondrial deficits in both MEFs and E18 cultured DRG neurons. Our study has revealed, for the first time, that expression of CMT2B Rab7 mutation at physiological level enhances Drp1 activity to promote mitochondrial fission, that may potentially underlie selective vulnerability of peripheral sensory neurons in CMT2B pathogenesis.

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Burst mitofusin activation reverses neuromuscular dysfunction in murine CMT2A

Cited by 41 publications

References 47 publications

MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons

MFN2 Deficiency Impairs Mitochondrial Transport and Downregulates Motor Protein Expression in Human Spinal Motor Neurons

Genetic Neuropathy Due to Impairments in Mitochondrial Dynamics

Mitochondria dysfunction in Charcot Marie Tooth 2B Peripheral Sensory Neuropathy

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