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The molecular determinants of mitochondrial transport

Mitochondria, known as the powerhouse of the cell, produce the energy required to drive most cellular functions. Therefore, delineating the mechanism behind mitochondrial trafficking will help understand mitochondria-related diseases.
The molecular determinants of mitochondrial transport
Mitochondria trafficking within the cell is regulated for spatiotemporal provision of ATP to power cell function. This takes place using motor proteins and adaptors found on the outer mitochondrial membrane. In metazoans, the outer mitochondrial membrane GTPase Miro forms complexes with dynein and kinesin proteins of microtubules and their TRAK adaptors to regulate mitochondrial distribution. Similarly, in lower eukaryotes, Miro is important for proper mitochondrial inheritance and viability.

Although the biochemical interactions of Miro proteins with other trafficking molecules and mitochondrial machinery are well characterised, little is known about the distribution of Miro proteins and their interactions with other key mitochondrial complexes. In answer to this, the EU-funded MITOTRAFFICBYMIRO (Differential role of atypical Rho GTPases Miro-1 and Miro-2 for controlling mitochondrial dynamics and transport) project investigated the interaction of Miro proteins with other key organelles, and delineated the molecular mechanisms implicated in mitochondrial distribution regulation.

Researchers identified new Miro-interacting partners including components of the mitochondrial inner membrane organising system. They also discovered that endogenous Miro protein may exist as dimers. Using stochastic optical reconstruction microscopy and structured illumination microscopy, they observed that Miro homodimers and heterodimers formed nanoclusters on the outer mitochondrial membrane.

The physical interaction between mitochondria and the endoplasmic reticulum (ER) was mediated by Miro proteins. In particular, Miro nanoclusters aligned with ER tubules and their loss disrupted contact and calcium transfer between the two organelles. Furthermore, Miro proteins interacted with the schizophrenia associated protein DISC1 and affected the ER-mitochondria contact area, underscoring its role in the communication between the two organelles.

Taken together, the MITOTRAFFICBYMIRO study unveiled the nanoscale organisation of Miro proteins in mitochondria, and provided mechanistic insight into their role in mitochondrial function. Importantly, the findings advance our current understanding of how mitochondrial trafficking controls diverse cellular functions and how its disruption may lead to disease.

Related information

Subjects

Life Sciences

Keywords

Mitochondria, Miro, MITOTRAFFICBYMIRO, endoplasmic reticulum, DISC1
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