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MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with α-tubulin acetylation and is disrupted in CMT2A

A. Kumar, D. Larrea, M.E. Pero, P. Infante, M. Conenna, G.J. Shin, W. B. Grueber, L. Di Marcotullio, E. Area-Gomez, View ORCID ProfileF. Bartolini
doi: https://doi.org/10.1101/2023.03.15.532838
A. Kumar
1Department of Pathology & Cell Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA
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D. Larrea
2Department of Neurology, Columbia University Irving Medical Center, 10032, New York, NY, USA
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M.E. Pero
1Department of Pathology & Cell Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA
3Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137, Naples, Italy
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P. Infante
4st, 00161, Rome, Italy
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M. Conenna
4st, 00161, Rome, Italy
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G.J. Shin
5Department of Neuroscience, Zuckerman Mind Brain Behavior Institute, Columbia University, 10027, New York, NY, USA
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W. B. Grueber
5Department of Neuroscience, Zuckerman Mind Brain Behavior Institute, Columbia University, 10027, New York, NY, USA
6Department of Physiology & Cellular Biophysics, Zuckerman Mind Brain Behavior Institute, Columbia University, 10032, New York, NY, USA
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L. Di Marcotullio
4st, 00161, Rome, Italy
7Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, Rome, Italy
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E. Area-Gomez
2Department of Neurology, Columbia University Irving Medical Center, 10032, New York, NY, USA
8Department de Biología Celular y Molecular, Centro de Investigaciones Biológicas, MARGARITA SALAS, CSIC, 28040, Madrid, Spain
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F. Bartolini
1Department of Pathology & Cell Biology, Columbia University Irving Medical Center, 10032, New York, NY, USA
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  • ORCID record for F. Bartolini
  • For correspondence: fb2131@columbia.edu
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Abstract

Acetylated microtubules play key roles in the regulation of mitochondria dynamics. It has however remained unknown if the machinery controlling mitochondria dynamics functionally interacts with the α-tubulin acetylation cycle. Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion, transport and tethering with the endoplasmic reticulum. The role of MFN2 in regulating mitochondrial transport has however remained elusive. Here we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through the MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). We discover that this activity is critical for MFN2-dependent regulation of mitochondria transport, and that axonal degeneration caused by CMT2A MFN2 associated mutations, R94W and T105M, may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in regulating acetylated α-tubulin and suggest that disruption of the tubulin acetylation cycle play a pathogenic role in the onset of MFN2-dependent CMT2A.

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Highlights

  • Mitochondria contacts with MTs are hotspots of α-tubulin acetylation through the recruitment of ATAT1 by MFN2

  • Mutations in MFN2 associated with CMT2A disease lose this activity by sequestering ATAT1

  • Distal axonal degeneration caused by loss of MFN2 depends on acetylated tubulin-mediated mitochondria transport

eTOC Recruitment of ATAT1 to mitochondria by MFN2 is critical for axonal viability through the regulation of mitochondria transport, and is disrupted in CMT2A

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    MT
    Microtubule
    PTMs
    post-translational modifications
    CMT2A
    Charcot-Marie-Tooth Type 2A
    MFN2
    Mitofusin-2
    ATAT1
    α-tubulin acetyl transferase 1
    HDAC6
    Histone deacetylase 6
    OMM
    outer mitochondrial membrane
    ER
    endoplasmic reticulum
    MFN1
    Mitofusin-1
    MAMs
    mitochondria-associated ER membranes
    TSA
    trichostatin A
    TTL
    tubulin tyrosine ligase
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    Posted March 16, 2023.
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    MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with α-tubulin acetylation and is disrupted in CMT2A
    A. Kumar, D. Larrea, M.E. Pero, P. Infante, M. Conenna, G.J. Shin, W. B. Grueber, L. Di Marcotullio, E. Area-Gomez, F. Bartolini
    bioRxiv 2023.03.15.532838; doi: https://doi.org/10.1101/2023.03.15.532838
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    MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with α-tubulin acetylation and is disrupted in CMT2A
    A. Kumar, D. Larrea, M.E. Pero, P. Infante, M. Conenna, G.J. Shin, W. B. Grueber, L. Di Marcotullio, E. Area-Gomez, F. Bartolini
    bioRxiv 2023.03.15.532838; doi: https://doi.org/10.1101/2023.03.15.532838

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