Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition

Kalinski, Ashley L.; Kar, Amar N.; Craver, John; Tosolini, Andrew P.; Sleigh, James N.; Lee, Seung Joon; Hawthorne, Alicia L.; Brito-Vargas, Paul; Miller-Randolph, Sharmina; Passino, Ryan; Shi, Liang; Wong, Venus; Picci, Cristina; Smith, Deanna S.; Willis, Dianna E.; Havton, Leif A.; Schiavo, Giampietro; Giger, Roman J.; Langley, Brett; Twiss, Jeffery L.

doi:10.1083/jcb.201702187

Cited by 91 publications

(89 citation statements)

References 78 publications

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“…Recent work has highlighted a new dimension of Miro regulation by acetylation. In this study, the authors initially noticed that inhibition of HDAC6 (histone deacetylase 6) promoted axonal growth . Upon closer examination, the authors determined that when HDAC6 deacetylated Miro, mitochondrial transport was inhibited.…”

Section: Miro Coordinates Mitochondrial Transport On Both Microtubulementioning

confidence: 99%

Miro: A molecular switch at the center of mitochondrial regulation

et al. 2020

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The orchestration of mitochondria within the cell represents a critical aspect of cell biology. At the center of this process is the outer mitochondrial membrane protein, Miro. Miro coordinates diverse cellular processes by regulating connections between organelles and the cytoskeleton that range from mediating contacts between the endoplasmic reticulum and mitochondria to the regulation of both actin and microtubule motor proteins. Recently, a number of cell biological, biochemical, and protein structure studies have helped to characterize the myriad roles played by Miro. In addition to answering questions regarding Miro's function, these studies have opened the door to new avenues in the study of Miro in the cell. This review will focus on summarizing recent findings for Miro's structure, function, and activity while highlighting key questions that remain unanswered.

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Section: Miro Coordinates Mitochondrial Transport On Both Microtubulementioning

confidence: 99%

Miro: A molecular switch at the center of mitochondrial regulation

et al. 2020

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“…Multiple authors have described that the mitochondrial Rho-GTPase-1 protein (Miro-1) is a crucial player in intercellular mitochondrial transfer via TNTs. Miro-1 is an outer mitochondrial membrane protein, that binds to Milton, a kinesin/dynein adaptor protein and this promotes mitochondrial motilit y [26,28,45,46]. We have now expanded this knowledge by showing that decreasing Miro-1 expression in astrocytes decreased the transfer of mitochondria from astrocytes to damaged neurons.…”

Section: Discussionmentioning

confidence: 98%

“…When endogenous protective mechanisms are not sufficient, interventions aimed at restoring mitochondrial health may provide additional help. Indeed, we showed recently that cell therapy with mesenchymal stem cells or a pharmacolgocial intervention with PFT-μ and HDAC6 inhibitor both reverse cisplatin-induced neuronal mitochondrial abnomarlities as well as cognitive impairment in mice [8,11,28,30,39,51,70].…”

Section: Discussionmentioning

confidence: 99%

“…Transfer of mitochondria from one cell to another occurs via multiple mechanisms such as release and uptake of vesicles, transfer via gap junctions, and transfer via F-actin based tunneling nanotubes [17,23]. Mitochondrial Rho-GTPase 1 (Miro-1) is a calcium-sensitive adaptor protein that drives movement of mitochondria along microtubules [24][25][26][27][28]. Miro-1 is involved in transferring mitochondria from mesenchymal stem cells to neuronal stem cells [20,29], but its contribution to mitochondrial transfer from astrocytes to neurons is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

English

Shepherd

Uzor

et al. 2020

acta neuropathol commun

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Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics that were characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in neurons that had received mitochondria from astrocytes which underlines the importance of mitochondrial transfer. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. We show that siRNA-mediated knockdown of the Rho-GTPase Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics. In conclusion, we showed that transfer of mitochondria from astrocytes to neurons rescues neurons from the damage induced by cisplatin treatment. Astrocytes are far more resistant to cisplatin than cortical neurons. We propose that transfer of functional mitochondria from astrocytes to neurons is an important repair mechanism to protect the vulnerable cortical neurons against the toxic effects of cisplatin.

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“…Since an increase in HDAC6 activity seems to be implicated in the pathogenesis of CMT2F [64], caused by mutations in HSPB1, d'Ydewalle and colleagues first tried HDAC6 inhibitors in a CMT2F transgenic mouse model, and the inhibitors corrected the axonal transport defects caused by HSPB1 mutation and reversed the CMT phenotype [65]. In addition, HDAC6 inhibition also appears to be capable of improving disrupted mitochondrial fusion and mitochondrial transport [66,67], and from this observation stemmed the idea of testing this strategy in CMT2A models as well. Indeed, in a recently published report, Picci and colleagues investigated the effect of pharmacological HDAC6 inhibition on MitoCharc1 mice [68], showing that the treatment was able to prevent alpha-tubulin hypoacetylation and rescue motor performance at both the pre-symptomatic and post-symptomatic stages.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Animal Models of CMT2A: State-of-art and Therapeutic Implications

et al. 2020

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Charcot–Marie–Tooth disease type 2A (CMT2A), arising from mitofusin 2 (MFN2) gene mutations, is the most common inherited axonal neuropathy affecting motor and sensory neurons. The cellular and molecular mechanisms by which MFN2 mutations determine neuronal degeneration are largely unclear. No effective treatment exists for CMT2A, which has a high degree of genetic/phenotypic heterogeneity. The identification of mutations in MFN2 has allowed the generation of diverse transgenic animal models, but to date, their ability to recapitulate the CMT2A phenotype is limited, precluding elucidation of its pathogenesis and discovery of therapeutic strategies. This review will critically present recent progress in in vivo CMT2A disease modeling, discoveries, drawbacks and limitations, current challenges, and key reflections to advance the field towards developing effective therapies for these patients.

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Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition

Cited by 91 publications

References 78 publications

Miro: A molecular switch at the center of mitochondrial regulation

Miro: A molecular switch at the center of mitochondrial regulation

Astrocytes rescue neuronal health after cisplatin treatment through mitochondrial transfer

Animal Models of CMT2A: State-of-art and Therapeutic Implications

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