Regulation of mitochondrial cristae organization by Myo19, Miro1/2 and Metaxin 3.

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 MICOS system. However, the interaction between Myo19, 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 Myo19 and Miro1/2's connection to MIB/MICOS. Deleting Miro1/2 mimics Myo19 deficiency effects on ER-mitochondria contacts and cristae structure, while 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.