Abstract
Mitochondrial rho GTPase (Miro) is a mitochondrial outer membrane protein containing two GTPase domains and two helix-loop-helix Ca2+-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, Ca2+ 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.
Highlights
CELLULAR NEUROSCIENCEThe myriad roles of Mitochondrial rho GTPase (Miro) in the nervous system: axonal transport of mitochondria and beyond
Mitochondrial rho GTPase (Miro) was initially identified by searching the public DNA and protein databases for novel members of the Rho GTPases family
The implication of Miro in the mitochondrial quality control process directed by the Pten-induced kinase 1 (PINK1)/Parkin pathway and in Parkinson’s disease (PD) pathogenesis opened up new directions for understanding the regulation and function of Miro in the nervous system, and raised the possibility that dysfunction of Miro may be broadly involved in the pathogenesis of other neurological disorders, where aberrant mitochondrial distribution, morphology, and function have been observed early in the disease process
Summary
The myriad roles of Miro in the nervous system: axonal transport of mitochondria and beyond. 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, Ca2+ 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.
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