Steven Sollott & Dmitry Zorov
talk with ScienceWatch.com and answer a few questions
about this month's Fast Moving Fronts paper in the field of
Agricultural Sciences.
Article: Mitochondrial ROS-induced ROS release: An
update and review
Authors: Zorov, DB;Juhaszova,
M;Sollott, SJ
Journal: BBA-BIOENERGETICS, 1757 (5-6): 509-517, MAY-JUN
2006
Addresses: Moscow MV Lomonosov State Univ, Dept Bioenerget, AN
Belozersky Inst, Moscow 119992, Russia.
Moscow MV Lomonosov State Univ, Dept Bioenerget, AN Belozersky
Inst, Moscow 119992, Russia.
NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD
21224 USA.
Why do you think your paper is highly
cited?
Damage to the cells of critical organs such as the heart or brain (e.g.,
due to a heart attack or stroke, respectively) is the primary cause of
morbidity and mortality in developed societies. Considerable scientific
efforts are thus being aimed at better understanding the nature of this
damage as well as investigating means of preventing or limiting it.
It has been increasingly recognized that the unwanted production of harmful
levels of reactive oxygen species (ROS) mediates much of the cellular
damage after a heart attack or stroke, and its source has become an area of
intense interest.
We found that the main energy-producing organelles, mitochondria, can
produce pathological levels of ROS inside injured cells that can spread
between mitochondria as a damaging wave throughout the cell via the
activation of a previously unrecognized positive-amplification cascade,
which we named, ROS-induced ROS release. We proposed that this is a
critical mechanism in certain forms of cell damage and death, an idea that
has gained increasing acceptance.
Does it describe a new discovery, methodology or
synthesis of knowledge?
The paper describes and extends the original discovery of ROS-induced ROS
release first published in an article entitled: "Reactive oxygen species
(ROS)-induced ROS release: a new phenomenon accompanying induction of the
mitochondrial permeability transition in cardiac myocytes," (Zorov DB,
et al., J. Exp. Med. 192[7]:1001-14, 2000).
Would you summarize the significance of your paper
in layman's terms?
Lead author: Dmitry Zorov
Mitochondria are abundant organelles residing inside each of the body's
cells that perform major functions, both in maintaining cellular health,
and, under certain circumstances, regulating or even causing their death.
They produce much of the energy needed to fuel vital cellular functions,
but in so doing also produce modest levels of some potentially toxic
byproducts, including highly reactive and potentially damaging forms of
oxygen ("ROS") that in healthy cells are rendered harmless by chemical
anti-oxidant mechanisms before they can cause any damage.
However, under certain circumstances, such as during a heart attack or
stroke, these mechanisms become very dysfunctional, so that the levels of
the toxic ROS can achieve levels that produce widespread damage, including
to the mitochondria themselves, rendering them unable to produce cellular
energy.
In addition, these toxic ROS levels can cause certain channels and/or large
pores in the mitochondrial membranes to open, resulting in an additional
large burst and release of toxic ROS that can spread to, and induce the
same destructive process in, the neighboring mitochondria, propagating like
a chain-reaction.
We named this previously unrecognized mechanism, mitochondrial ROS-induced
ROS release. This self-amplifying mechanism operates as a positive-feedback
loop that can produce a wave of destructive ROS spreading throughout the
cell, causing widespread damage and destruction of mitochondria and other
sensitive targets which can ultimately kill the cell.
This damage to the cells, often irreversible and resulting in their death,
is what causes the relatively permanent and serious dysfunction of the
heart or brain after a heart attack or stroke, respectively. This mechanism
has also been linked to arrhythmias of the heart, which together with loss
of functional cells, can contribute to the significant morbidity and
mortality of heart attacks.
Insights gained from understanding the nature of this mechanism can lead to
more effective treatments to limit the damage due to diseases such as heart
attacks and strokes.
How did you become involved in this research and
were any particular problems encountered along the way?
Mitochondria had been extensively studied for decades before our research,
mainly using biochemical techniques. Our experiments required the use of
advanced, laser-based confocal microscopy techniques together with probes
of vital organelle function that would not have been available even a few
years before we conducted our project.
Also, the mechanisms we were proposing required a certain revision to
long-standing dogma about the ability of mitochondria to produce ROS under
certain conditions, which we had to overcome.
In particular, in the case we were examining, under the circumstances when
we found that the mitochondria produce a ROS-burst, most of the world's
mitochondrial experts would have predicted that ROS formation would be
virtually absent, let alone demonstrating some kind of increase.
Our experimental interpretations were met with some initial skepticism, but
soon our findings were reproduced by several independent laboratories in
other parts of the world, and these ideas have been gaining increasing
acceptance in the fields of mitochondrial and cell biology.
Where do you see your research leading in the
future?
We have found that the mechanisms we are examining are significantly
affected during the aging process. Furthermore, heart attacks and strokes,
while vastly more prevalent with age, are also more severe in the elderly.
We anticipate that this research might lead to understanding what are the
critical variables involved in the aging process, and to be able to develop
more effective treatments to limit the damage due to serious diseases of
the elderly, such as heart attacks and strokes.
Steven J. Sollott, M.D.
Head, Cardioprotection Unit
Laboratory of Cardiovascular Science
Gerontology Research Center
National Institute on Aging
Intramural Research Program
Baltimore, MD, USA Web
Dmitry B. Zorov, Ph.D.
Adjunct Investigator
Cardioprotection Unit
Laboratory of Cardiovascular Science
Gerontology Research Center
National Institute on Aging
Intramural Research Program
Baltimore, MD, USA
and
Head, Laboratory of the structure and function of mitochondria
Department of Bioenergetics
A.N. Belozersky Institute of Physico-Chemical Biology
Moscow State University
Moscow, Russia
Why do you think your paper is highly
cited?
