Caltech-led team uncovers new functions of mitochondrial fusion

[Guest guest]

(Note: Chan has done extensive work on CMT 2 and the mitochondria)

Caltech-led team uncovers new functions of mitochondrial fusion

Finds that cells without mitochondrial fusion have less mtDNA, more mutations in

their mtDNA, and less ability to tolerate those mutations

http://www.eurekalert.org/pub_releases/2010-04/ciot-ctu041410.php

PASADENA, Calif.— A typical human cell contains hundreds of

mitochondria—energy-producing organelles—that continually fuse and divide.

Relatively little is known, however, about why mitochondria undergo this

behavior.

In a paper published in the April 16 issue of the journal Cell, a team of

researchers—led by scientists at the California Institute of Technology

(Caltech)—have taken steps toward a fuller understanding of this process by

revealing just what happens to the organelle, its DNA (mtDNA), and its

energy-producing ability when mitochondrial fusion fails. In the process, the

researchers show that fusion (the merging of two mitochondria) is " highly

protective, allowing the mitochondria to tolerate very high loads of

mitochondrial DNA mutations, " says Chan, associate professor of biology at

Caltech and a Medical Institute (HHMI) investigator.

These findings, Chan adds, help to shed light on the pathogenesis behind human

mitochondrial encephalomyopathies—a class of neuromuscular diseases caused by

mutations in mtDNA. In these diseases, muscle weakness occurs due to the loss of

energy production by mitochondria.

When first discovered, mitochondrial fusion was thought simply to control the

shape of mitochondria. And indeed, Chan says, that is at least partially the

case. " If you don't have fusion to balance division, the mitochondria get

smaller and smaller as they divide, " he explains.

But what hadn't been appreciated in the past, he says—and what the research

described in the Cell paper makes clear—is that these smaller mitochondria

undergo much more than a cosmetic change. " We've showed that in mammalian cells,

there are physiological consequences if there's no mitochondrial fusion, " says

Chan.

To show just what happens, the team created mice with defects in two proteins

known as mitofusins—mfn1 and mfn2—which are located on the surface of the

mitochondria and are essential to the process of fusion. " We were able to

specifically delete these mitofusins in skeletal muscle, " Chan explains.

As it turns out, when fusion is blocked, not only are the mitochondria smaller,

but the mtDNA levels in the mitochondria drop precipitously. As for the mice

themselves? While they are born looking relatively normal, over the next couple

of months they show signs that something is going wrong. Their growth is

severely stunted and they die by 7-8 weeks of age, just at the onset of

adulthood.

The mtDNA that remains in these unfused mitochondria " has a higher accumulation

of point mutations and deletions, " says Chan. In other words, without fusion,

the mtDNA contains more mistakes, suggesting that fusion is " necessary for mtDNA

stability. "

This work may be important to our understanding of how and why human

mitochondrial encephalomyopathies come to pass. Scientists have noted that most

cells have a remarkably high tolerance for the mtDNA mutations that cause these

conditions; in fact, somewhere between 60 and 90 percent of mtDNA has to carry

the mutation before symptoms will begin to appear in a person with the mtDNA

mutation. " Cells can tolerate a very high load of mtDNA mutations, " Chan notes.

Why? Possibly because each cell carries so many copies of mtDNA that the

" normal " versions are able to make up for the miscues of the mutated

versions—but only if the mitochondria are able to fuse and combine their

contents from time to time.

Chan and colleagues showed this to be the case in another set of experiments, in

which they looked at a mouse model known to carry a high number of mtDNA

mutations. Due to these mtDNA mutations, Chan explains, the mouse line has a

lifespan less than half that of a normal mouse.

Still, it could be much worse—as Chan and colleagues showed when they tweaked

the mouse model so that its mitochondria could no longer fuse. " When we added

the mfn1 mutation into this model, we found that the mice died at birth instead

of surviving to one year of age, " he says. These results suggest that

mitochondrial fusion is highly protective in cells carrying mtDNA mutations, as

would be the case in encephalomyopathies.

Now that they've identified the problems that lack of fusion cause, the team

plans to address the mechanisms by which these issues arise. " Why is there less

mtDNA? " asks Chan. " Why is there less fidelity in the mtDNA genome? That's what

we're going to study now. "

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In addition to Chan, the other authors on the Cell paper, " Mitochondrial Fusion

is Required for mtDNA Stability in Skeletal Muscle and Tolerance of mtDNA

Mutations, " are Caltech senior research scientist Hsiuchen Chen; Marc Vermulst,

formerly a postdoctoral scholar at Caltech now at the University of North

Carolina, Chapel Hill; Caltech graduate student Yun beth Wang; Anne Chomyn,

an HHMI research specialist and senior research associate emerita at Caltech;

Tomas Prolla from the University of Wisconsin, Madison; and J. McCaffery

from the s Hopkins University.

Their work was funded by an RO1 grant from the National Institutes of Health

(NIH), an Ellison Medical Foundation Senior Scholar Award, and a grant from the

NIH's National Center for Research Resources.