Mitochondria, energy-generating organelles, snake throughout the insides of cells in an interconnected network. “People often think of mitochondria as static organelles that work alone,” says HHMI investigator David Chan, “but they constantly fuse and divide. No one really understood why these events happen, or how, until the last 10 years.”

Chan, at the California Institute of Technology, studies how the cell achieves a balance in its mitochondria network. If fusion overwhelms fission, the mitochondria become excessively long and connected, eventually “collapsing into a messy jumble,” says Chan. And if fission overwhelms fusion, the organelles are dramatically fragmented and less efficient at producing energy. It's a delicate balance.

When geneticists at Duke University linked a mitochondrial fusion gene to a neurological disease, Chan wondered how a defect in mitochondrial fusion might lead to peripheral neuropathy, which causes numbness and weakness in the hands and feet. Chan engineered mice that lacked the implicated fusion gene, mitofusin2. He found defects in the mitochondria of the Purkinje cells, a class of neurons in the brain known for the dramatic fan of fibers that branch off them. With crippled mitochondrial fusion machinery, the arbor of fibers was reduced to short stumps.

Looking closer at the mitochondrial membranes, Chan saw fragmented organelles, not the interconnected network that ought to be there. Furthermore, mitochondria usually contain their own DNA—mtDNA. “But in this fragmented mutant, only a fraction of them have mtDNA,” Chan says. The observation of missing DNA explains why fragmented mitochondria can't produce energy—they lack the DNA that encodes proteins controlling energy generation. Neurons may be particularly sensitive to these defects, because the cells are among the most energy demanding. His lab is pursuing the link between mitochondrial fission and fusion and mtDNA, since mtDNA defects are associated with additional pathological conditions.

On a computer screen, when membrane fission and fusion are slowed down, they appear to be straightforward processes. Press play and the membranes move. The merging of membranes looks fluid and natural, like it requires no molecular machinery at all. After all, two soap bubbles can join together without the help of proteins. But inside the cell, as these researchers have shown, taking away a piece of the membrane's control mechanisms leads to a messy jumble of membranes, or a stand-still in vesicle creation—and both problems have unmistakable links to disease.

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