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

• Type of Material: Article
• Authors: Ashley L Kalinski, Drexel University; Amar N Kar, University of South Carolina, Columbia; John Craver, University of South Carolina, Columbia; Andrew P Tosolini, University College London; James N Sleigh, University College London; Seung Joon Lee, University College London; Alicia Hawthorne, Emory University; Paul Brito-Vargas, University of South Carolina, Columbia; Sharmina Miller-Randolph, University of South Carolina, Columbia; Ryan Passino, University of Michigan; Liang Shi, University of South Carolina, Columbia; Victor SC Wong, Burke Neurological Institute; Cristina Picci, Burke Neurological Institute; Deanna S Smith, University of South Carolina, Columbia; Dianna E Willis, Burke Neurological Institute; Leif A Havton, University of California Los Angeles; Giampietro Schiavo, University College London; Roman J Giger, University of Michigan; Brett Langley, Burke Neurological Institute; Jeffery L Twiss, University of South Carolina, Columbia
• Language: English
• Date: 2019-06-01
• Publisher: ROCKEFELLER UNIV PRESS
• Publication Version: Final Published Version
• Copyright Statement: © 2019 Kalinski et al.
• License: Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1083/jcb.201702187
• Title of Journal or Parent Work: JOURNAL OF CELL BIOLOGY
• Volume: 218
• Issue: 6
• Start Page: 1871
• End Page: 1890
• Keywords: MICROTUBULES; MOTILITY; HISTONE-DEACETYLASE; ACETYLATION; MOTOR; NEURITE GROWTH; Life Sciences & Biomedicine; Science & Technology; REGENERATION; Cell Biology; RHO; IN-VITRO; TUBULIN
• Research Categories: Biology, Cell

Abstract

Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelinassociated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases axonal mitochondrial transport. HDAC6 inhibition increases acetylated Miro1 in axons, and acetyl-mimetic Miro1 K105Q prevents CSPG-dependent decreases in mitochondrial transport and axon growth. MAG- and CSPG-dependent deacetylation of Miro1 requires RhoA/ROCK activation and downstream intracellular Ca2+ increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca2+. These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport.