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Science Forum Index » Medicine Forum » Iron-saturated Ferritin Mediates Myocardial Injury...
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| ironjustice... |
 Posted: Thu Jul 03, 2008 6:17 pm |
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The Involvement of Lysosomes in Myocardial Aging and Disease
Alexei Terman, Tino Kurz, Bertil Gustafsson and Ulf T. Brunk
The myocardium is mainly composed of long-lived postmitotic cells
with, if there is any at all, a very low rate of replacement through
the division and differentiation of stem cells.
As a consequence, cardiac myocytes gradually undergo pronounced age-
related alterations which, furthermore, occur at a rate that inversely
correlates with the longevity of species. Basically, these alterations
represent the accumulation of structures that have been damaged by
oxidation and that are useless and often harmful.
These structures (so-called ‘waste’ materials), include defective
mitochondria, aberrant cytosolic proteins, often in aggregated form,
and lipofuscin, which is an intralysosomal undegradable polymeric
substance.
The accumulation of ‘waste’ reflects the insufficient capacity for
autophagy of the lysosomal compartment, as well as the less than
perfect functioning of proteasomes, calpains and other cellular
digestive systems.
Senescent mitochondria are usually enlarged, show reduced potential
over their inner membrane, are deficient in ATP production, and often
produce increased amounts of reactive oxygen species.
The turnover of damaged cellular structures is hindered by an
increased lipofuscin loading of the lysosomal compartment.
This particularly restricts the autophagic turnover of enlarged,
defective mitochondria, by diverting the flow of lysosomal hydrolases
from autophagic vacuoles to lipofuscinloaded lysosomes where the
enzymes are lost, since lipofuscin is not degradable by lysosomal
hydrolases.
As a consequence, aged lipofuscin-rich cardiac myocytes become
overloaded with damaged mitochondria, leading to increased oxidative
stress, apoptotic cell death, and the gradual development of heart
failure.
Defective lysosomal function also underlies myocardial degeneration in
various lysosomal storage diseases, while other forms of
cardiomyopathies develop due to mitochondrial DNA mutations, resulting
in an accumulation of abnormal mitochondria that are not properly
eliminated by autophagy.
The degradation of iron-saturated ferritin in lysosomes mediates
myocardial injury in hemochromatosis, an acquired or hereditary
disease associated with iron overload.
Lysosomes then become sensitized to oxidative stress by the overload
of low mass, redox-active iron that accumulates when iron-saturated
ferritin is degraded following autophagy.
Lysosomal destabilization is of importance in the induction and/or
execution of programmed cell death (either classical apoptotic or
autophagic), which is a common manifestation of myocardial aging and a
variety of cardiac pathologies.
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Tom
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