A squatter parasite resides in every cell of everybody'sbody. At least, that's one way of looking at themitochondrion, a cell's source of energy.
Back in the early days of life on earth, so this conceptgoes, a free-living bacterium broke into a precursor celland set up housekeeping. One DNA replication led toanother, and ever since then, mitochondrial organelleshave powered every cell in the animal kingdom, whilechloroplasts do as much for the plant world.
Several lines of evidence support this hypothesis thatmitochondria are the descendants of that entrapped _ ordomesticated _ free-living microbe. For one thing,mitochondria possess their own private genome, with itsown genes expressing its own few proteins. For another,the gene that encodes the organelle itself exist only in thefemale of the species. Ergo, every mitochondrial gene,and the product it expresses, hark back to a maternalprogenitor only.
When a mitochondrial gene mutates, its deformedproduct can cause degeneration of specific human tissues.If the mutation is severe, the lesion may arise early in itsvictim's life; a milder lesion takes its tissue toll at a moreadvanced age.
Such is the case of Alzheimer's disease, which comes intwo discrete forms _ early-onset, and late-onset. Arecent multi-center study linked this two-stage pattern toa mutant gene on the mitochondrial genome. Thedefective gene reportedly occurred more frequently inAlzheimer's and Parkinson's disease victims than in thegeneral population.
That 1993 report in the journal Genomics (17, 171-184)blamed this effect on an adenine-to-guanine pointmutation of the mitochondrial translation RNA forglutamine at position 4336.
Researcher Compares Autopsied Brains
To test and measure this notion, molecular biologist GinoCortopassi at the University of Southern California set upa case-control study, comparing autopsied Alzheimer'sbrain tissue with that of non- Alzheimer's controls. Hisreport in the current Proceedings of the NationalAcademy of Sciences (PNAS), dated July 18, bears thetitle: "A mitochondrial DNA clone is associated withincreased risk for Alzheimer disease."
In 72 Alzheimer's brains, Cortopassi found the 4336Gmutation in six individuals. In 480 controls, only threehad it _ less than 1 percent. But of this number, the 296in the Alzheimer age bracket of 50 to 104 years, a singlecontrol sample carried the mutation, and "this individualwas 79 years old with no history of dementia." All of thepatients studied were Caucasians.
The six Alzheimer's cases with the mutant gene averaged67.8 years of age at onset of dementia, compared to 71 forall other Alzheimer's patients studied. The latter died at81.3 years on average; the former at 79 years.
Statistical analysis of this data, the PNAS paperconcludes, indicated that persons over 50 years of agewith the 4336G mutation have a 27-fold increased risk ofdeveloping mitochondrial Alzheimer's.
Alzheimer's and Parkinson's are not the only afflictionscaused by mutations of the mitochondrial genome. Othersinclude sensorineural deafness, ataxia andcardiomyopathy. These reflect serious defects in theelectron transport chain, by which mitochondria pump outconstant stepwise pulses of energy to power the rest ofthe cell.
Oxidative Damage May Play Key Role
Harvard neurologist Flint Beal, a co-author of thatGenomics paper, told the Society for Neurosciencemeeting last November in Miami that "Oxidative damageto DNA may play a role in both normal aging and inneurodegenerative diseases," notably Alzheimer's."Mitochondria," he observed, "are the major source offree radicals in the cell."
Research fellow Susan Browne, who works with Beal,focusing on the mechanism of this mitochondrial injury,told BioWorld Today that such oxidative damage may setoff a chain reaction, literally, beginning with alteration ofthe electron transport chain, thus diminishing ATP, thecell's major energetic product, and allowing extracellularglutamate to flood into the cell, leading to excitotoxic celldeath.
As for the possible role of amyloid protein inAlzheimer's, Browne is "not 100 percent convinced thatamyloid induces cell death." She terms this hypothesis "asource of great debate in a fashion-driven field."
Less than one-tenth of 1 percent of people under 40exhibit the symptoms of Alzheimer's, the paper pointsout, but more than 20 percent of persons 85 or older do.
Extrapolating from the 7 percent incidence heencountered among his Alzheimer's case tissue samples,and assuming 210 million Caucasians in the U.S.population, he concluded that about 1.5 millionAmericans "are at excess risk for developing`mitochondrial Alzheimer's disease' in their lifetime, as aresult of bearing the 4336G mutation."
But in a brief subsequent statement, Cortopassi added:"Further studies will be necessary to confirm thesignificance of the results in a wide segment of the U.S.population." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.