Discovery in CMT cell death

September 21, 2004

Key Cell-Death Step Found September 21, 2004

A fundamental cellular event related to programmed cell death has been

decoded by cell biologists at UC and s Hopkins University. The

work could provide insights on two devastating inherited diseases.

In healthy cells, mitochondria (tiny energy substations that churn out

each cell's power supply) continually fuse together and split in two.

When mitochondrial fusion goes awry, cells are targeted for programmed

cell death, or apoptosis.

Apoptosis is a normal process in healthy individuals, but if

mitochondrial fusion doesn't work, the wrong cells die, causing disease.

This is what happens in two neurodegenerative diseases: dominant optic

atrophy, the most common inherited cause of blindness, and

Charcot-Marie-Tooth disease, which reduces sensation in the feet, lower

legs and hands. Both diseases kill nerve cells.

Until recently, scientists knew these diseases were triggered by a

problem with mitochondrial fusion, but didn't understand fusion itself,

says Jodi Nunnari, a UC professor of molecular and cellular

biology.

Mitochondrial fusion was tricky to understand because mitochondria are

structurally complex, Nunnari said. A mitochondrion looks a bit like an

orange -- an outer membrane, analogous to the orange peel, contains it,

while a different type of membrane on the inside facilitates the

mitochondria's functions. Scientists wondered how two mitochondria could

join without mixing up the distinct membranes.

Nunnari's team devised ways to get stop-action views of fusion and

follow the process in isolated mitochondria. They saw two distinct

stages. First, outer membranes joined, creating an intermediate

structure with one outer membrane holding two sets of inner membranes.

Then, the inner membranes fused. The researchers also were able to

investigate some of the biochemical requirements for the process.

The work is published in the Sept. 17 issue of Science.

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