11.16.2006

Eating Lipids to Fuse Mitos

A couple of weeks back I wrote about dynamins and mitochondrial fusion. Well the latest piece of the puzzle came in ... I just saw a paper in the latest Nature Cell Biology on this very topic. Apparently a mitochondrial version of phospholipase D (MitoPLD) may act downstream of the dynamin like molecule Mfn1 to promote fusion of the outer mitochondrial membrane.

Now remember mitos have two membranes. If two mitos want to get together they must fuse the outer membranes. This requires a dynamin protein (Mfn1 in mammals). After this fusion the two inner mitochondrial membranes can come together and fuse (this second fusion requires yet another dynamin like molecule). Also remember that some dynamins can form spirals and/or rings in vitro. This is weird as dynamins are thought to form spirals the can pinch and thus break off membranes (just like spiral collar around your neck would decapitate you by squeezing your neck and pushing your head away from your torso).

Back to the paper ...

Most of the assays in the paper are at the cellular level (looking for mito aggregates and/or fragmentation), although the authors do confirm that MitoPLD converts cardiolipin to phophatydic acid (PA). Also it looks like Mfn1 first tethers two mitos together and then mitoPLD performs some key step that activates membrane fusion. Beyond this simple explanation things are still murky.

mitofusion.jpg

How can mitoPLD stimulate this activity? From the paper:

The requirement for production of phosphatidic acid is reminiscent of the requirement for classic PLD-dependent generation of phosphatidic acid in SNARE-mediated fusion of secretory vesicles with the plasma membrane during many types of regulated exocytosis3, 4 and during sporulation in yeast11. Taken together, these findings reveal a common requirement for a specific manipulation of the lipid environment despite the lack of conservation of the associated protein machinery and mechanism of action. The role of phosphatidic acid remains undetermined -- it may facilitate fusion by generating negative curvature in the opposing bilayers, by recruiting or activating other key proteins or enzymes, or by being further converted to other fusogenic lipids (such as diacylglycerol). Interestingly, phosphatidic acid has been shown to recruit Spo20, the yeast homologue of the mammalian t-SNARE 25, to sites of vesicle fusion through direct interaction28, and to accelerate the rate of mammalian SNARE-driven vesicle fusion in vitro29.


So PA may just promote fusion and may act in several fusion events in cells. Or here is a crazy idea, maybe mitoPLD dissolves some mito membrane (by digesting cardiolipin) and acts as a hole puncher on the mitochondrial outer membrane. This hole puncher activity might be locally contained within Mfn1 rings (see the pic above and the dynamin entry). After the holes are punched, the Mfn1 rings could serve as connector between the two mitos fixtures thus serving as a temporary channel between mitos. The outer membranes of adjacent mitos could then mix ... and presto fusion is complete!

Now of course there are lots of problems. Mfn1 is not known to form rings. There isn't that much cardiolipin in mito membranes and this would be a very messy way of fusing the outer mito membranes ... in any case I'm sure we're missing many components that will shed new light to this process.

(Also there is a discussion as to how this process of mito fusion may be connected to apoptosis [i.e. regulated cell death]. Didn't have time to reread up the background, but I'd thought I'd mention it.)

ref:

Seok-Yong Choi, Ping Huang, Gary M. Jenkins, David C. Chan, Juergen Schiller & Michael A. Frohman
A common lipid links Mfn-mediated mitochondrial fusion and SNARE-regulated exocytosis
Nature Cell Biology (06) 8:1255-1262
doi:10.1038/ncb1487

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