Mitochondria isolated from bovine heart cells were prepared for sectioning and imaged with a JEOL1230 transmission electron microscope. The image shows a mitochondria-derived vesicle (MDV) emerging from the intact mitochondrion. Scale bar is 20 nm. Image courtesy of H. McBride, University of Ottawa Heart Institute, Canada.

An unexpected intracellular transport route between mitochondria and peroxisomes has been identified by Heidi McBride and co-workers. Reporting in Current Biology, they describe and characterize mitochondria-derived vesicles (MDVs), which can incorporate selected cargo and fuse with peroxisomes in a cargo-specific manner.

The authors were interested in identifying proteins that regulate mitochondrial morphology. Because this morphology can be regulated by ubiquitylation and sumoylation, they used a bioinformatics screen to search for candidate ubiquitin or small ubiquitin-like modifier (SUMO) E3 ligases that contain conserved RING domains and are anchored into mitochondria.

An unexpected intracellular transport route between mitochondria and peroxisomes has been identified...

This approach led to the identification of a new outer-membrane mitochondria-anchored protein ligase (MAPL) that contains a RING domain. McBride and colleagues showed that MAPL overexpression resulted in mitochondrial fragmentation, which is consistent with a role for MAPL in the control of mitochondrial morphology. This fragmentation was dependent on both the RING domain of MAPL and the presence of the mitochondrial fission GTPase dynamin-related protein-1 (DRP1).

Interestingly, however, when the authors studied cells expressing a dominant-negative mutant of DRP1 and either wild-type MAPL or MAPL lacking the RING domain, they observed a pool of highly uniform, 70–100-nm-diameter vesicular structures within the otherwise highly interconnected mitochondrial reticulum. These structures resemble intracellular transport vesicles, and the fact that they contain either MAPL or another outer-mitochondrial-membrane marker, translocase of outer membrane 20kDa subunit (TOM20), indicates that they selectively incorporate their cargo.

Using time-lapse confocal microscopy and fluorescently labelled MAPL, the authors observed the formation of these vesicles in real time. In addition to the expected general mitochondrial fragmentation, they observed a few unique fission events that involved the lateral enrichment of MAPL along the tubular mitochondria, followed by the pinching off of the enriched region to form a spherical mitochondrial fragment or MDV. These events are distinct from previously described mitochondrial fission events, which involve whole-organelle constriction.

To determine the fate of MDVs, the authors tested several cellular markers and found that MAPL-positive vesicles colocalize with peroxisomes, whereas TOM20-positive vesicles do not. Furthermore, using time-lapse imaging, they directly observed a MAPL-positive MDV fusing with a peroxisome. It therefore seems that cargo is a primary determinant of MDV fate.

So, the work of McBride and colleagues has identified MAPL — a novel mitochondrial outer-membrane protein that participates in the regulation of DRP1-mediated mitochondrial fission in a RING-domain-dependent manner. Their work has also provided the first evidence that mitochondrial cargo (including MAPL) can be sorted into highly uniform MDVs, which form independently of DRP1. Furthermore, the fact that MAPL-positive MDVs fuse with peroxisomes has provided “...a direct link between two organelles that are known to operate in a highly coordinated manner”. The next question is to determine the real function of this transport event.