[biomed] mitochondria gone bad

[Eugen Leitl]

http://www.sciencenews.org/view/feature/id/40762/title/Mitochondria_Gone_Bad

Mitochondria Gone Bad

Problems in the cell’s energy factories power new ideas on disease and aging

By Laura Beil

February 28th, 2009; Vol.175 #5 (p. 20)

Mitochondria are among the small structures called organelles that reside
within a cell. Known as the cells’ powerhouses, mitochondria extract energy
from fuels such as glucose in the presence of oxygen to produce a molecule
called adenosine triphosphate, or ATP (green), which provides energy for the
cell. In the process, mitochondria generate potentially dangerous free
radicals (red).Illustration: Nicolle Rager Fuller

The patient, known as only “MBM,” was just 7 years old the first time doctors
saw her. She had always been prone to night sweats, but now excessive
perspiration was forcing her to change clothes several times a day. She was
endlessly thirsty, fatigued and losing weight despite a voracious appetite. A
dozen years later, at age 19, doctors checked her into a hospital, thinking
she had some kind of unusual metabolic condition. After aggressive treatment
with drugs, her symptoms improved, but only for a short time, and the next
year surgeons removed most of her thyroid. When she was 35 — gaunt, weak and
losing hair — doctors began searching every tissue of her body for a
diagnosis.

They finally located the problem. It was MBM’s mitochondria, the organelles
that supply the energy for cells to function. Thanks to mitochondria, the
sandwich you had for lunch is now powering your heart and brain. Somehow the
mitochondria inside MBM’s cells had gone haywire, becoming too large and too
numerous. Such damage was “the first instance of a spontaneous functional
defect of the mitochondrial enzyme organization.” The mysterious case of
patient MBM was considered so remarkable that the Journal of Clinical
Investigation published a description of it. That was in 1962.

Today, scientists suspect that millions of people may be suffering from
mitochondria gone awry, in more subtle but nonetheless insidious forms.
Evidence suggests that malfunctioning mitochondria could explain Alzheimer’s
disease, Parkinson’s, diabetes, cardiovascular disease, obesity, cancer and
other consequences of aging. Given the organelle’s core function in the body,
some think mitochondria might even be the biological epicenter of aging
itself: If you live long enough, all your cells might experience a kind of
energy crisis. “I strongly believe that mitochondrial metabolism is the key
to aging,” says Hemachandra Reddy of Oregon Health & Science University in
Beaverton.

Even before scientists suspected a role in common diseases, mitochondria had
some biological celebrity. The sometimes tubular, sometimes bean-shaped
structures are remnants of an ancient bacterium captured by a one-celled
organism more than a billion years ago, experts believe. In animal cells,
mitochondria are the only cellular components outside the nucleus that boast
their own DNA, which is passed on from mother to child almost in its
entirety. Douglas Wallace of the University of California, Irvine, a
self-described “mitochondriac,” has used variations in mitochondrial DNA to
help construct a global human family tree, tracing the migration of ancient
humans from Africa.

These days, however, Wallace concerns himself with the living. “All these
diseases that no one has been able to solve might be solved by understanding
the mitochondria,” he says. This is, he contends, a new way of thinking about
illness. “Up until very recently, mitochondria were considered very arcane
and certainly not part of mainstream medicine,” he says. Questions about
mitochondria were mostly confined to rare brain and muscle syndromes linked
to inherited defects in the organelles.

In a move that will push mitochondria studies further into the mainstream,
this year the National Institutes of Health has put aside grant money to
encourage more mitochondria research, hoping to “transform our understanding
of the role of this critical organelle in human health and disease,”
according to the funding announcement. Already scientists have found clues
that link defects in mitochondria to Alzheimer’s disease, Parkinson’s, heart
failure and other breakdowns in the body that come with age.

The price of energy

While scientists have theorized for at least three decades that mitochondria
might be the basis for aging, renewed interest has come from the growing
realization that a mitochondrion is more than just a cellular furnace.
Mitochondria’s main purpose is indeed energy production — they make molecules
of adenosine triphosphate, or ATP, the gasoline of a cell. But these energy
factories also flip the levers on other functions, such as protecting against
highly damaging incarnations of oxygen known as free radicals, orchestrating
chemical communication within a cell and triggering the natural death of
cells that become broken down or aged. Still, skeptics point out that there’s
not enough evidence yet to conclude whether mitochondria are the causes of
illness, the victims of it or just innocent bystanders.

Free radical damage has long been suspected as a culprit in aging, and
mitochondria are both the primary source of free radicals in a cell and the
main protection against them. “As you get older, the number of mitochondria
that are not functioning increases,” says Mark Mattson, chief of the National
Institute on Aging’s Laboratory of Neurosciences in Baltimore. Over time,
mutations accumulate in mitochondrial genes. These and other changes may
cause the power plants to work less efficiently, producing less energy for
the same amount of glucose — the way a less energy-efficient car travels
fewer miles on a tank of gas. Cells eventually become less able to rid
themselves of these defective mitochondria. As life goes on, the body moves
closer to a brownout — or so says the mitochondrial aging theory.

In nerve cells, mitochondria are key to the growth of axons and dendrites,
which send and receive signals from other cells. Antioxidants that target
mitochondria may protect cells and spur axon and dendrite development: An
untreated mouse nerve cell (left) shows less growth than does a cell treated
with the antioxidant MitoQ (right).P. Hemachandra Reddy

Mattson points out that the only known way to extend life span, at least in
animal experiments, is through calorie restriction. Studies have found that
mice fed very-low–calorie diets live longer than their better-fed brethren.
While the explanation is still under study, Mattson says that such food
restriction may affect mitochondria most acutely, putting the organelles
under stress. The stress forces mitochondria to operate more efficiently. In
a state of slight starvation, “the mitochondria maintain their function
longer, and they also seem to produce less free radicals,” he says.

To examine the efficiency of old mitochondria, researchers from the
University of Washington Medical Center in Seattle measured whether
mitochondria from older muscle cells work as well as mitochondria from
younger ones. The investigators followed the production of ATP, the energy
molecule, along with oxygen consumption In the body, food is broken down into
sugar molecules called glucose; mitochondria use oxygen to convert glucose
into ATP. Older muscles seem to struggle with ATP production, the scientists
reported in 2007 in Proceedings of the National Academy of Sciences.

“In aging muscles, there is a mitochondria dysfunction,” says Seattle
researcher David Marcinek. “They produce less ATP for the same amount of
oxygen consumed.”

In Mattson’s view, and that of other researchers who suspect that people are
only as young as their mitochondria, mild amounts of stress force
mitochondria to make better use of the glucose available — whether that
stress is from calorie restriction or another source. Stress also causes
cells to produce proteins that protect the mitochondria from free radical
damage. And Mattson points out that other conditions that strain energy
production — such as physical and mental activity — also appear to strengthen
tissues at the same time.

He points to other lines of evidence linking mitochondria to aging. For
example, mice bred to have deletions in a gene called PolgA, which encodes an
enzyme critical for the replication of mitochondrial DNA, experience
accelerated aging, including hair loss, weight loss and curvature of the
spine. More recently, in the journal Science, Wallace and his colleagues
reported that a mutation in the mitochondrial genes of mice led to heart
failure, a disease that becomes more common with age, even when the DNA in
the cell nucleus remained unaffected.

Death in the brain

If mitochondria are the architects of aging, they may also be responsible for
some of the most notorious afflictions of old age. Mitochondria aren’t
distributed evenly in the body. A cell may have a few dozen of them or a few
thousand, depending on the energy demand. Not surprisingly, the diseases most
under scrutiny for a mitochondrial origin are those involving tissues that
consume a lot of energy, and therefore maintain small armies of mitochondria.
And a particularly greedy organ — consuming about 20 percent of the body’s
energy — is the brain.

In the December issue of the journal NeuroMolecular Medicine, Reddy makes the
case for Alzheimer’s being a mitochondrial disease. For starters, it now
appears that brain cells involved in Alzheimer’s show damage from free
radicals early in the disease process. Studies have found decreased
production of mitochondrial enzymes in the brains of Alharm mitochondria.

Once scientists figure out the cause of mitochondrial problems, the hope is
to devise a way to prevent or repair the damage. For those with congenital
mitochondrial disease, doctors have no cures, only symptom relief. But
clinical trials are underway for some age-related diseases. One is looking at
whether high doses of an antioxidant that acts in the mitochondria, coenzyme
Q-10, might slow disease progression in Parkinson’s patients.

In the case of patient MBM, researchers offer no hint about how long she
survived, or how well, after doctors discovered the source of her problem. No
one knows how she died, but maybe one day scientists will understand how she
lived.

Laura Beil is a freelance science writer in Cedar Hill, Texas.