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Regulation of mitochondrial cristae organization by Myo19, Miro1 and Miro2, and metaxin 3

Samruddhi S Shembekar¹, Petra Nikolaus¹, Ulrike Honnert¹

¹Institute of Integrative Cell Biology and Physiology, University of Münster, 48149 Münster, Germany.

Journal of Cell Science

|January 30, 2025

Abstract:

The actin-based motor myosin-19 (Myo19) exerts force on mitochondrial membrane receptors Miro1/2, influencing endoplasmic reticulum (ER)-mitochondria contact sites and mitochondrial cristae structure. The mitochondrial intermembrane bridging (MIB) complex connects the outer and inner mitochondrial membranes at the cristae junction through the mitochondrial contact site and cristae organization system (MICOS). However, the interaction between Myo19, Miro1 and Miro2 (hereafter Miro1/2), and the MIB-MICOS complex in cristae regulation remains unclear. This study investigates the roles of Miro1/2 and metaxin 3 (Mtx3), a MIB complex component, in linking Myo19 to MIB-MICOS. We show that Miro1/2 interact with Myo19 and the MIB complex but not with Mtx3. Their mitochondrial membrane anchors are not essential for MIB interaction or cristae structure. However, Mtx3 is crucial for the connection between MIB-MICOS and the Myo19 and Miro1/2 proteins. Deleting Miro1/2 mimics the effects of Myo19 deficiency on ER-mitochondria contacts and cristae structure, whereas Mtx3 deletion does not. Notably, the loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, reducing cardiolipin and its precursors, suggesting Myo19 and Miro1/2 influence cristae indirectly via lipid transfer at ER-mitochondria contact sites.

Insights

Myosin-19 (Myo19) and Miro1/2 proteins regulate mitochondrial structure by interacting with the MIB-MICOS complex. This interaction influences endoplasmic reticulum-mitochondria contacts and lipid composition, impacting cristae organization.

Area of Science:

Cell Biology
Mitochondrial Dynamics
Membrane Contact Sites

Background:

Myosin-19 (Myo19) interacts with Miro1/2 receptors, affecting ER-mitochondria contacts and mitochondrial cristae.
The MIB-MICOS complex organizes mitochondrial cristae junctions.
The precise roles of Myo19, Miro1/2, and MIB-MICOS in cristae regulation are not fully understood.

Purpose of the Study:

To investigate the roles of Miro1/2 and Mtx3 in linking Myo19 to the MIB-MICOS complex.
To elucidate the mechanisms by which Myo19 and Miro1/2 influence mitochondrial structure and function.

Main Methods:

Co-immunoprecipitation assays to study protein interactions.
Mitochondrial morphology analysis using electron microscopy.
Lipidomic analysis of mitochondrial cardiolipin and its precursors.

Main Results:

Miro1/2 interact with Myo19 and the MIB complex, but not Mtx3.
Mtx3 is essential for connecting MIB-MICOS with Myo19 and Miro1/2.
Deletion of Miro1/2 phenocopies Myo19 deficiency effects on ER-mitochondria contacts and cristae structure.
Loss of Myo19 and Miro1/2 alters mitochondrial lipid composition, decreasing cardiolipin.

Conclusions:

Mtx3 is crucial for linking Myo19 and Miro1/2 to the MIB-MICOS complex.
Myo19 and Miro1/2 indirectly regulate cristae structure, potentially via lipid transfer at ER-mitochondria contact sites.
Mitochondrial lipid composition is influenced by Myo19 and Miro1/2 activity.

Read full analysis

Keywords:

Cristae organization ER–mitochondria contact sites Lipid transfer Mitochondria Myosin Rho GTPases

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