Mitochondrial Miro GTPases coordinate mitochondrial and peroxisomal dynamics

Abstract

Mitochondria and peroxisomes are highly dynamic, multifunctional organelles. Both perform key roles for cellular physiology and homoeostasis by mediating bioenergetics, biosynthesis, and/or signalling. To support cellular function, they must be properly distributed, of proper size, and be able to interact with other organelles. Accumulating evidence suggests that the small atypical GTPase Miro provides a central signalling node to coordinate mitochondrial as well as peroxisomal dynamics. In this review, I summarize our current understanding of Miro-dependent functions and molecular mechanisms underlying the proper distribution, size and function of mitochondria and peroxisomes.

Keywords: Miro; Small GTPase; membrane dynamics; mitochondria; mitochondrial dynamics; motility; peroxisomal dynamics; peroxisome.

Figure 1.

Protein architecture of Miro. (a). Schematic representation of Miro’s GTPase and ELM domains consisting of an EF hand, a ‘hidden’ EF-hand and LM helix. The transmembrane domain (TM), acetylation (red; K92, K512, and K616) and phosphorylation sites (Polo (orange): S59; PINK1 (yellow): S156, T298, and T299) of Miro1 are indicated. (b). Protein variants (1–4) of human Miro1 derived from alternative mRNA splicing of exons 19 and 20, which causes small insertions of 32 (green) and 41 residues (yellow), respectively. Variants 2 and 4 exhibit a preferred peroxisomal localization, while variants 1 and 3 are mostly localized to mitochondria. Panel 1A was adapted with permission from [35], panel 1B was adapted from [224]

Figure 2.

Architecture of the basic Miro-TRAK motor adaptor complex. Miro-TRAK motor adaptor complexes orchestrate coordinated transport of both mitochondrial membranes. Miro proteins are tail-anchored in the OMM and recruit TRAK proteins to mitochondria. Miro and TRAK proteins interact with Kinesin motors while only TRAKs recruit dynein-dynactin motors. In addition, Miro links MT motors to the OMM and IMM by interacting with components of MIB complexes, which consist of linked MICOS and SAM complexes in the IMM and OMM, respectively. OGT associates with and post-translationally modifies TRAKs regulating transport

Figure 3.

Architecture of Miro-TRAK-DISC scaffold complex. Miro/TRAK complexes link mitochondria to kinesin and dynein-dynactin motors. DISC1 robustly associates with TRAK1/2. NDE1 and GSK3β associate with TRAKs and DISC1. DISC1 scaffolds comprised of NDE1 and GSK3β may associate with Miro-TRAK motor complexes to modulate mitochondrial transport. Figure was adapted with permission from [125]

Figure 4.

Conceptual model of arresting MT-based mitochondrial transport to enable efficient mitophagy. Miro-TRAK complexes facilitate transport of healthy mitochondria via kinesin and dynein. Under normal conditions, Miro is associated with a small pool of Parkin. Following mitochondrial depolarization, PINK1 accumulates on the OMM, LRRK2 associates with Miro, and the small pool of Parkin associated with Miro becomes activated to accelerate recruitment and activation of cytosolic Parkin if Miro is Ca²⁺-bound to remove an unknown constraint of Parkin recruitment. Subsequent proteasomal degradation of ubiquitinated Miro arrests mitochondrial transport and enables mitophagy to proceed efficiently

Figure 5.

Miro-dependent mitochondrial recruitment and stabilization of actin motors. The actin motor Myo19 consists of a head domain (bright green), a neck region, and a short tail (yellow-green), which contains a lipid binding motif to associate with the OMM, and a Miro1/2 binding motif at the extreme C-terminus. In the absence of Miro interactions, Myo19 insertions into the OMM are rare and proteasomal Myo19 degradation is favoured (a). Interactions with Miro link Myo19 to mitochondria and increase the probability of inserting the lipid binding motif into the OMM (b). Miro interactions and/or OMM insertions then protect Myo19 from proteasomal degradation. Figure was adapted with permission from [188]

Figure 6.

Miro-dependent stabilization of mitochondria-ER contact sites. Ca²⁺ released from the ER through IP₃Rs can be sequestered at mito-ER contacts into the mitochondrial matrix through VDAC in the OMM and the GRP75-linked MCU in the IMM. Polo kinase-mediated phosphorylation of Miro (dMiro: S66; human Miro1: S59) promotes its interaction with mito-ER contacts and regulates their structural integrity. Figure was adapted with permission from [47]