Miro proteins coordinate microtubule and actin dependent mitochondrial transport and distribution Guillermo López-Doménech1, Christian Covill-Cooke1, Davor Ivankovic1, Els F. Halff1, David F. Sheehan1, Rosalind Norkett1, Nicol Birsa1, and Josef T. Kittler1 1Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK.
In the current model of mitochondrial trafficking, Miro1 and Miro2 Rho-GTPases regulate mitochondrial transport along microtubules by linking mitochondria to kinesin and dynein motors. By generating Miro1/2 double knockout mouse embryos and single and double knockout embryonic fibroblasts, we demonstrate the essential and non-redundant roles of Miro proteins for embryonic development and subcellular mitochondrial distribution. Unexpectedly, the TRAK1 and TRAK2 motor-protein adaptors can still localise to the outer mitochondrial membrane to drive anterograde mitochondrial motility in Miro1/2 double knockout cells. In contrast, TRAK2-mediated retrograde mitochondrial transport is Miro1-dependent. Furthermore, we find that Miro proteins are critical for recruiting and stabilising the mitochondrial myosin Myo19 on the mitochondria for coupling mitochondria to the actin cytoskeleton. Moreover, Miro depletion during PINK1 / Parkin-dependent mitophagy can also drive a loss of mitochondrial Myo19 upon mitochondrial damage. Finally, aberrant positioning of mitochondria in Miro1/2 double knockout cells leads to disruption of correct mitochondrial segregation during mitosis. Thus, Miro proteins can fine tune actin and tubulin-dependent mitochondrial motility and positioning to regulate key cellular functions such as cell proliferation.
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