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

Bernard-Marissal, Nathalie; Hameren, Gerben van; Juneja, Manisha; Pellegrino, Christophe; Louhivuori, Lauri; Bartesaghi, Luca; Rochat, Cylia; Mansour, Omar El; Médard, Jean-Jacques; Croisier, Marie; Maclachlan, Catherine; Poirot, Olivier; Uhlén, Per; Timmerman, Vincent; Tricaud, Nicolas; Schneider, Bernard L.; Chrast, Roman

doi:10.1073/pnas.1810932116

Cited by 79 publications

(83 citation statements)

References 70 publications

(122 reference statements)

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“…Finally, R94Q MFN2 appears to lead to reduction in MERCS in CMT2A patient-derived fibroblasts, in primary neurons and in vivo in motoneurons of the above-mentioned mouse model of CMT2A [16]. This was associated with increased ER stress, Ca2+ handling defects, and changes in the geometry and axonal transport of mitochondria [16].…”

Section: Züchner Et Al Originally Identified a Heterozygous 281g-a Tmentioning

confidence: 94%

“…The authors concluded that neuropathic conditions uncouple the production of reactive oxygen species (ROS) and ATP thereby potentially compromising axonal function and integrity [15]. Finally, R94Q MFN2 appears to lead to reduction in MERCS in CMT2A patient-derived fibroblasts, in primary neurons and in vivo in motoneurons of the above-mentioned mouse model of CMT2A [16]. This was associated with increased ER stress, Ca2+ handling defects, and changes in the geometry and axonal transport of mitochondria [16].…”

Section: Züchner Et Al Originally Identified a Heterozygous 281g-a Tmentioning

confidence: 99%

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

Wolf¹,

R²,

Thaher³

et al. 2019

Preprint

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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 similar mitochondrial oxygen consumption, membrane potential and ATP production. Mild oxidative stress procured by 100 µM hydrogen peroxide applied 24 h before analysis, however, significantly increased respiration but decreased mitochondrial ATP production only in R94Q cells. This was accompanied by increased glucose uptake and an upregulation of hexokinase 1 and pyruvate kinase M2 suggesting increased pyruvate shuttling into mitochondria. As these changes coincided with decreased levels of PINK1/Parkin-mediated mitophagy in R94Q cells, we conclude that the disease-causing R94Q mutation in MFN2 causes uncoupling of mitochondrial respiration from ATP production by a less efficient mitochondrial quality control.

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Section: Züchner Et Al Originally Identified a Heterozygous 281g-a Tmentioning

confidence: 94%

Section: Züchner Et Al Originally Identified a Heterozygous 281g-a Tmentioning

confidence: 99%

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

Wolf¹,

R²,

Thaher³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Thus, mitochondrial dysfunction in oligodendrocytes could be responsible for the observed lack of G-ratio adaption to axonal mitochondria dysfunction. To address this, mice with axonal-specific mutations in the mitochondria protein Mtf2 (here referred to as Ax:Mfn2) were assessed [2]. However, similar to the full-body mutated strains (Opa Mut+/+ and Afg3L2 +/+ ) the axon-surrounding myelin failed to adapt in the Ax:Mfn2 +/+ in response to dysfunctional axonal mitochondria, thus leaving the Gratio unchanged compared to wild-type (Ax:Mfn2 -/-) (Fig.3A, D, E).…”

Section: Axonal Mitochondria Adapt the Diameter To Dysregulated Myelimentioning

confidence: 99%

Axonal mitochondria across species adjust in diameter depending on thickness of surrounding myelin

Ineichen

Zhu

Carlström

2019

Preprint

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In the central nervous system (CNS), axons and its surrounding myelin sheaths, generated by oligodendrocytes, greatly depend on each other, where oligodendrocytes provide axons with both trophic and metabolic support. Across spices, assessment of the axon-myelin ultrastructure is the key-approach to visualize de-and re-myelination of axons. However, this assessment omits to provide information on axonal homeostasis or how axon-myelin influence one another. Since mitochondria may adjust in size thus mirroring the intracellular physiological and metabolic status we applied this to myelinated axons in the CNS. We herein show that a large axonal mitochondria diameter correlates with thinner surrounding myelin sheaths across different CNS tracts and species, including human. We also show that the relation between axonal mitochondria diameter and surrounding myelin thickness is a valuable measurement to verify advanced remyelination in two commonly used experimental demyelinating models, namely the cuprizone and the lysolecithin (LPC) model. Lastly, we show that axonal mitochondria adjust in diameter in response to the thickness of the axonal surrounding myelin whereas the opposite adaption was absent. In summary, the link between axonal mitochondria diameter and surrounding myelin thickness provide insight on the axon-myelin relation both during homeostasis and pathological conditions. This link is also translational applicable and can thus contribute to a better understanding on how to study remyelination using experimental models.

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“…However, while control mice mitochondria increased their ATP production further following a second stimulation, no increase was observed in mutant mice mitochondria. We have shown that Mitochondria Associated Membranes (MAM), which mediate interactions between the endoplasmic reticulum and mitochondria [41], are impaired in these mutant mice. So we suggest that an impaired Ca 2+ uptake by mitochondria through MAM [61] could alter the ATP production as it has been shown that calcium is required for the TCA cycle [62].…”

Section: Discussionmentioning

confidence: 99%

“…We recently showed that MFN2 R94Q mice, a model for CMT2A disease [25] where MFN2 is defective, displayed altered mitochondria motility and clustering in peripheral nerve axons [41]. We used this model to measure the level of ATP in axonal mitochondria of myelinated axons in neuropathic conditions.…”

Section: Atp and H2o2 Production Are Altered In Cmt2a Neuropathic Micementioning

confidence: 99%

CMT disease 2A and demyelination decouple ATP and ROS production by axonal mitochondria

Campbell

Deck

et al. 2018

Preprint

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Mitochondria are critical for the function and maintenance of myelinated axons notably through ATP production. A by-product of this activity is reactive oxygen species (ROS), which are highly deleterious for neurons. While ROS and metabolism are involved in several neurodegenerative diseases, it is still unclear how axonal activity or myelin modulates ATP and ROS production in axonal mitochondria. We imaged and quantified mitochondrial ATP and hydrogen peroxide (H 2 O 2 ) in resting or stimulated peripheral nerve myelinated axons in vivo, using genetically-encoded fluorescent probes, two-photon time-lapse and CARS imaging. ATP and H 2 O 2 productions are intrinsically higher in nodes of Ranvier even in resting conditions. Axonal firing increased both ATP and H 2 O 2 productions but with different dynamics. In neuropathic MFN2 R94Q mice, mimicking Charcot-Marie-Tooth 2A disease, defective mitochondria failed to upregulate ATP production following axonal activity.However, H 2 O 2 production was dramatically sustained. Mimicking demyelinating peripheral neuropathy resulted in a reduced production of ATP while H 2 O 2 level soared. Taken together, our results suggest that ATP and ROS productions are decoupled under neuropathic conditions, which may compromise axonal function and integrity.

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

Cited by 79 publications

References 70 publications

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

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

Axonal mitochondria across species adjust in diameter depending on thickness of surrounding myelin

CMT disease 2A and demyelination decouple ATP and ROS production by axonal mitochondria

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