The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond

Abstract

Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca(2+)-binding domains called EF hands. Pioneering genetic studies in Drosophila first revealed a key function of Miro in regulating the axonal transport of mitochondria, during which Miro forms a multi-protein transport complex with Milton and Kinesin heavy chain (KHC) to link trafficking mitochondria with the microtubule (MT) cytoskeleton. Recent studies showed that through binding to the EF hands of Miro and causing conformational changes of Miro and alteration of protein-protein interactions within the transport complex, Ca(2+) can alter the engagement of mitochondria with the MT/kinesin network, offering one mechanism to match mitochondrial distribution with neuronal activity. Despite the importance of the Miro/Milton/Kinesin complex in regulating mitochondrial transport in metazoans, not all components of the transport complex are conserved in lower organisms, and transport-independent functions of Miro are emerging. Here we review the diverse functions of the evolutionarily conserved Miro proteins that are relevant to the development, maintenance, and functioning of the nervous system and discuss the potential contribution of Miro dysfunction to the pathogenesis of diseases of the nervous system.

Keywords: apoptosis; calcium homeostasis; microtubule dynamics; mitochondria-ER communication; mitochondrial morphogenesis; mitochondrial motility; mitochondrial rho GTPase.

Figure 1

Diagram depicting possible roles of Miro in the nervous system. (A) Miro forms a complex with Milton and kinesin heavy chain to mediate mitochondrial transport along the microtubule cytoskeleton. (B) Miro influences mitochondrial morphology, presumably through its interaction with Mitofusins or some unknown factors. (C) Miro regulates the integrity or function of the mitochondria-ER contact sites, which mediate calcium transfer from the ER to mitochondria through calcium transporters. (D) Miro regulates microtubule dynamics through an unknown mechanism. This aspect of Miro function may affect the cell cycle and division of neural stem cells.