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

Kumar, A.; Larrea, D.; Pero, M. E.; Infante, P.; Conenna, M.; Shin, G. J.-e.; Grueber, W. B.; Di Marcotullio, L.; Area-Gomez, E.; Bartolini, F.

doi:10.1101/2023.03.15.532838

bioRxiv · 10.1101/2023.03.15.532838

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

Kumar, A.·Larrea, D.·Pero, M. E.·Infante, P.·Conenna, M.·Shin, G. J.-e.·Grueber, W. B.·Di Marcotullio, L.·Area-Gomez, E.·Bartolini, F.

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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 -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 -tubulin acetylation, which occurs through the MFN2-mediated recruitment of -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 -tubulin and suggest that disruption of the tubulin acetylation cycle play a pathogenic role in the onset of MFN2-dependent CMT2A. O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/532838v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@3db8eorg.highwire.dtl.DTLVardef@143821corg.highwire.dtl.DTLVardef@1132b13org.highwire.dtl.DTLVardef@1710383_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMitochondria contacts with MTs are hotspots of -tubulin acetylation through the recruitment of ATAT1 by MFN2 C_LIO_LIMutations in MFN2 associated with CMT2A disease lose this activity by sequestering ATAT1 C_LIO_LIDistal axonal degeneration caused by loss of MFN2 depends on acetylated tubulin-mediated mitochondria transport C_LI eTOCRecruitment of ATAT1 to mitochondria by MFN2 is critical for axonal viability through the regulation of mitochondria transport, and is disrupted in CMT2A

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Kumar, A., Larrea, D., Pero, M. E., Infante, P., Conenna, M., Shin, G. J.-e., Grueber, W. B., Di Marcotullio, L., Area-Gomez, E., Bartolini, F.. 2023-03-16. MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A. https://doi.org/10.1101/2023.03.15.532838

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