Sci. Aging Knowl. Environ., 23 April 2003
Vol. 2003, Issue 16, p. nw60
[DOI: 10.1126/sageke.2003.16.nw60]


Mitochondrial Mayhem

Alzheimer's protein disarms the cell's energy plant

R. John Davenport;2003/16/nw60

Key Words: cytochrome c oxidase • translocase • transmembrane arrest • respiration

Like a protester who's chained herself to the gate of a nuclear power plant, a protein implicated in Alzheimer's disease (AD) adheres to a cell's power generator and prevents normal operations, according to new work. The study makes the first direct connection between the protein and the malfunctions in energy production that appear in AD.

Inside brain cells of people with AD, mitochondria--the cell's energy-generating machines--go haywire through an unknown mechanism. Plaques of {beta}-amyloid protein outside neurons characterize AD, but some researchers think that the aggregates result from, rather than cause, the illness. Still, {beta} amyloid and its molecular relatives are strongly implicated in the condition; familial forms of AD arise from mutations in genes that encode amyloid precursor protein (APP), which undergoes processing to release {beta} amyloid, and enzymes that clip it.

New work links APP to mitochondrial mayhem. Biochemist Narayan Avadhani of the University of Pennsylvania in Philadelphia and colleagues discovered that APP harbors a string of amino acids that sends other proteins to mitochondria. To test whether APP migrates to that organelle, the scientists separated cellular compartments of neurons engineered to produce copious amounts of APP and looked for the protein. Besides appearing at its known haunts--the cell's secretion apparatus and outer membrane--APP attached to mitochondria. Altering the targeting code kept APP away from mitochondria. Additional experiments revealed that the protein enters and clogs pores in the membrane that surrounds mitochondria.

The team next assessed how APP affects mitochondrial function. As the organelles accumulated APP, they produced fewer molecules of the cellular fuel ATP, reduced the activity of an energy-generating enzyme, and lost the gradient of ions across their membrane that drives ATP production. When cells made the APP variants that shun mitochondria, the organelles functioned normally even though {beta} amyloid accumulated. The group then analyzed mice that had been engineered to make extra APP. Cells from the animals--which amass amyloid plaques in their brains--carried more APP in their mitochondria and generated less ATP than did cells from normal animals. The result suggests that superfluous APP blockades mitochondria in intact animals, perhaps instigating trouble. By obstructing membrane pores, APP might prevent essential proteins from entering mitochondria and cripple energy production independently of {beta}-amyloid production, says Avadhani. He wants to investigate whether APP also spurs cells to commit suicide, a process that starts in mitochondria.

"It's a very solid piece of work," says neurologist Flint Beal of Weill Medical College of Cornell University in New York City. Connecting APP to mitochondria is "a very important link" in understanding AD, he says. The next step, continues Beal, is to determine how APP's disruption of mitochondria relates to plaque accumulation. "Mitochondrial damage seems to be one of the earliest signs of neuronal impairment [in AD]," says neurochemist Laura Canevari of University College London in the U.K. The results "offer a valid explanation of how this may happen." The study also lends credence to the idea that amyloid proteins inside the cell, rather than outside, trigger AD, she adds. Understanding how APP's dissent closes down mitochondria could reveal ways of keeping peace in the brain.

--R. John Davenport

April 23, 2003
  1. H. K. Anandatheerthavarada, G. Biswas, M.-A. Robin, N. G. Avadhani, Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell Biol. 161, 41-54 (2003).[Abstract/Free Full Text]
Citation: R. J. Davenport, Mitochondrial Mayhem. Sci. SAGE KE 2003, nw60 (23 April 2003);2003/16/nw60

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