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

Autor:	Kalinski AL; Department of Biology, Drexel University, Philadelphia, PA.; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI., Kar AN; Department of Biological Sciences, University of South Carolina, Columbia, SC., Craver J; Department of Biological Sciences, University of South Carolina, Columbia, SC., Tosolini AP; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK., Sleigh JN; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute, University College London, London, UK., Lee SJ; Department of Biological Sciences, University of South Carolina, Columbia, SC., Hawthorne A; Department of Cell Biology, Emory University, Atlanta, GA., Brito-Vargas P; Department of Biological Sciences, University of South Carolina, Columbia, SC., Miller-Randolph S; Department of Biological Sciences, University of South Carolina, Columbia, SC., Passino R; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI., Shi L; Department of Biological Sciences, University of South Carolina, Columbia, SC., Wong VSC; Burke Neurological Institute, White Plains, NY., Picci C; Burke Neurological Institute, White Plains, NY., Smith DS; Department of Biological Sciences, University of South Carolina, Columbia, SC., Willis DE; Burke Neurological Institute, White Plains, NY., Havton LA; Departments of Neurology and Neurobiology, University of California, Los Angeles, Los Angeles, CA., Schiavo G; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK.; UK Dementia Research Institute, University College London, London, UK.; Discoveries Centre for Regenerative and Precision Medicine, University College London Campus, London, UK., Giger RJ; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI., Langley B; Burke Neurological Institute, White Plains, NY., Twiss JL; Department of Biological Sciences, University of South Carolina, Columbia, SC twiss@mailbox.sc.edu.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2019 Jun 03; Vol. 218 (6), pp. 1871-1890. Date of Electronic Publication: 2019 May 08.
DOI:	10.1083/jcb.201702187
Abstrakt:	Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated 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 Ca 2+ increase, and Miro1 K105Q prevents the decrease in axonal mitochondria seen with activated RhoA and elevated Ca 2+ These data point to HDAC6-dependent deacetylation of Miro1 as a mediator of axon growth inhibition through decreased mitochondrial transport. (© 2019 Kalinski et al.)
Databáze:	MEDLINE
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