The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration

Cartoni, Romain; Norsworthy, Michael; Bei, Fengfeng; Wang, Chen; Li, Siwei; Zhang, Shujun; Gabel, Christopher V.; Schwarz, Thomas L.; He, Zhongshi

doi:10.1016/j.neuron.2017.04.028

Cited by 35 publications

(34 citation statements)

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“…This observation is supported by recent work reporting an interaction between TRAK1 and both mitofusins (Lee et al, 2017). We cannot rule out that other candidates like Mfn2, DISC1, syntaphilin or the Armcx family of proteins (Misko et al, 2010;Lopez-Domenech et al, 2012;Chen & Sheng, 2013;Cartoni et al, 2016;Norkett et al, 2016), all of them shown to regulate mitochondrial transport, may also be able to interact with and recruit TRAK proteins in the absence of Miro.…”

Section: Discussionsupporting

confidence: 64%

Miro proteins coordinate microtubule‐ and actin‐dependent mitochondrial transport and distribution

et al. 2018

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In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho‐GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double‐knockout mouse embryos and single‐ and double‐knockout embryonic fibroblasts, we demonstrate the essential and non‐redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double‐knockout cells. In contrast, we show that TRAK2‐mediated retrograde mitochondrial transport is Miro1‐dependent. Interestingly, we find that Miro is critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1/Parkin‐dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double‐knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine‐tune actin‐ and tubulin‐dependent mitochondrial motility and positioning, to regulate key cellular functions such as cell proliferation.

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Section: Discussionsupporting

confidence: 64%

Miro proteins coordinate microtubule‐ and actin‐dependent mitochondrial transport and distribution

et al. 2018

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“…Of interest, a recent optic nerve injury study found that the mitochondrial transport regulator Armcx1 (Armadillo Repeat Containing, X-Linked 1) is up-regulated in retinal ganglion cells (RGCs) after knockout of PTEN and SOCS3, another tumor suppressor that limits axon regeneration. Overexpression of Armcx1 enhanced mitochondrial transport in RGC axons and knockdown completely blocked axon regeneration induced by PTEN and SOCS3 knockout (Cartoni et al, 2016). These studies highlight the importance of the axonal trafficking machinery in ensuring sufficient support for regenerative axon growth.…”

Section: Axonal Traffickingmentioning

confidence: 68%

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

Kaplan

Bueno

Hua

et al. 2017

Developmental Dynamics

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The failure of damaged axons to regrow underlies disability in central nervous system injury and disease. Therapies that stimulate axon repair will be critical to restore function. Extensive axon regeneration can be induced by manipulation of oncogenes and tumor suppressors; however, it has been difficult to translate this into functional recovery in models of spinal cord injury. The current challenge is to maximize the functional integration of regenerating axons to recover motor and sensory behaviors. Insights into axonal growth and wiring during nervous system development are helping guide new approaches to boost regeneration and functional connectivity after injury in the mature nervous system. Here we discuss our current understanding of axonal behavior after injury and prospects for the development of drugs to optimize axon regeneration and functional recovery after CNS injury.

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“…Manipulation of mitochondrial density within these injuried axons greatly influenced their regenerative ability, in which increasing mitochondrial density within the axons promoted regeneration, whereas reducing their density inhibited axonal regeneration. In rodent models, the knockout of the mitochondria stop signaling protein syntaphilin was shown to enhance regeneration of sciatic nerve axons; whereas, overexpression of the Armadillo Repeat Containing X-Linked 1 (Armcx1) protein (Cartoni et al, 2016), which is thought to aid tethering of the mitochondrial membrane with the Miro1 adaptor protein, enhanced optic nerve regeneration after injury. In the latter paper, overexpression of Armcx1 was shown to promote axonal regeneration alone and further enhance the general regenerative ability of neurons after knockdown of PTEN, a regeneration inhibitory signaling protein, indicating an important role of mitochondria in the regenerative growth process within the CNS.…”

Section: Enhancing Mitochondria Bioenergentics And/or Transport Facilmentioning

confidence: 99%

The role of mitochondria in axon development and regeneration

Smith

Gallo

2017

Developmental Neurobiology

132

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Mitochondria are dynamic organelles that undergo transport, fission, and fusion. The three main functions of mitochondria are to generate ATP, buffer cytosolic calcium, and generate reactive oxygen species. A large body of evidence indicates that mitochondria are either primary targets for neurological disease states and nervous system injury, or are major contributors to the ensuing pathologies. However, the roles of mitochondria in the development and regeneration of axons have just begun to be elucidated. Advances in the understanding of the functional roles of mitochondria in neurons had been largely impeded by insufficient knowledge regarding the molecular mechanisms that regulate mitochondrial transport, stalling, fission/fusion, and a paucity of approaches to image and analyze mitochondria in living axons at the level of the single mitochondrion. However, technical advances in the imaging and analysis of mitochondria in living neurons and significant insights into the mechanisms that regulate mitochondrial dynamics have allowed the field to advance. Mitochondria have now been attributed important roles in the mechanism of axon extension, regeneration, and axon branching. The availability of new experimental tools is expected to rapidly increase our understanding of the functions of axonal mitochondria during both development and later regenerative attempts. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 221-237, 2018.

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The Mammalian-Specific Protein Armcx1 Regulates Mitochondrial Transport during Axon Regeneration

Cited by 35 publications

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Miro proteins coordinate microtubule‐ and actin‐dependent mitochondrial transport and distribution

Miro proteins coordinate microtubule‐ and actin‐dependent mitochondrial transport and distribution

Maximizing functional axon repair in the injured central nervous system: Lessons from neuronal development

The role of mitochondria in axon development and regeneration

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