MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A
Atul Kumar,
Delfina Larrea,
Maria Elena Pero,
Paola Infante,
Marilisa Conenna,
Grace J. Shin,
Vincent Van Elias,
Wesley B. Grueber,
Lucia Di Marcotullio,
Estela Area-Gomez,
Francesca Bartolini
Affiliations
Atul Kumar
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
Delfina Larrea
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA
Maria Elena Pero
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Veterinary Medicine and Animal Production, University of Naples Federico II, 80137 Naples, Italy
Paola Infante
Department of Molecular Medicine, University of Rome “La Sapienza”, 00161 Rome, Italy
Marilisa Conenna
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Molecular Medicine, University of Rome “La Sapienza”, 00161 Rome, Italy
Grace J. Shin
Department of Neuroscience, Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
Vincent Van Elias
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
Wesley B. Grueber
Department of Neuroscience, Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Physiology & Cellular Biophysics, Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA
Lucia Di Marcotullio
Department of Molecular Medicine, University of Rome “La Sapienza”, 00161 Rome, Italy; Istituto Pasteur-Fondazione Cenci Bolognetti, University of Rome La Sapienza, Rome, Italy
Estela Area-Gomez
Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA
Francesca Bartolini
Department of Pathology & Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Corresponding author
Summary: 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 and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.
