Miro: A molecular switch at the center of mitochondrial regulation

Abstract

The orchestration of mitochondria within the cell represents a critical aspect of cell biology. At the center of this process is the outer mitochondrial membrane protein, Miro. Miro coordinates diverse cellular processes by regulating connections between organelles and the cytoskeleton that range from mediating contacts between the endoplasmic reticulum and mitochondria to the regulation of both actin and microtubule motor proteins. Recently, a number of cell biological, biochemical, and protein structure studies have helped to characterize the myriad roles played by Miro. In addition to answering questions regarding Miro's function, these studies have opened the door to new avenues in the study of Miro in the cell. This review will focus on summarizing recent findings for Miro's structure, function, and activity while highlighting key questions that remain unanswered.

Keywords: GTPase; Miro; microtubule transport; mitochondria; neurodegeneration; organelle contact sites.

Figure 1

Structural features of Miro. (a) Domain organization. (b) Annotated primary sequence of Miro. Black “+” indicates constitutively active GTP mutant whereas “*” indicates constitutively inactive GTP mutant. Blue “*” indicate mutations in EF‐hands that block calcium binding. (c) Model of Miro structure based on published coordinates of Miro's nGTPase (PDB: 6D71) and the C‐terminus of Miro (PDB: 5KSZ)

Figure 2

Miro mediates organelle–cytoskeleton and organelle–organelle contact sites. Miro contributes to diverse cellular activities involved in organelle–cytoskeleton contacts (peroxisome–microtubule, mitochondria–microtubule, & mitochondria–actin) as well as organelle–organelle contacts (ER–mitochondria & mitochondria–mitochondria)

Figure 3

Miro‐directed transport of mitochondria. (a) Receptors localized on outer mitochondrial membrane. (b) Regulatory factors that influence transport on microtubules and actin. (c) Motor protein machinery required for transport. (d) Example receptor‐motor complexes docked onto mitochondria & cytoskeletal elements

Figure 4

Potential model of mitochondrial clearance via mitophagy. Under normal cellular conditions, Miro directs microtubule‐based transport via kinesin and dynein. Note that Miro is also pre‐bound to Parkin. (1) Mitochondrial damage (e.g., membrane depolarization) occurs. (2) Following damage, LRRK2 is activated and phosphorylates Miro. (3) Once phosphorylated by LRRK2, PINK1 phosphorylates Miro in addition to Parkin. (4) Parkin ubiquitinates Miro. (5) Mitophagy clears damaged mitochondria. Note that mutations to LRRK2, PINK1, and Parkin (denoted “*”) in addition to α‐synuclein accumulation likely inhibits this process to prevent mitochondrial clearance