Grants and Contracts Details
Description
Recent work suggests that mitochondrial dysfunction plays a central role in sepsis, a major cause of
death and morbidity in the United States. The underlying mechanisms responsible for this mitochondrial
dysfunction are not known. The goal of the present proposal is to test the hypothesis that increased free
radical generation in sepsis produces specific biochemical, structural and genetic changes that result in
marked physiologic alterations in mitochondrial function. We postulate: (a) mitochondrial dysfunction in
sepsis results from physiologic derangements of Krebs cycle enzymes, Complex I-IV electron transport
chain components, and sarcomeric creatine kinase, (b) these physiologic changes are due, in turn, to
alterations in the content and composition of mitochondrial proteins, and (c) protein changes are due, in
part, to free radical-mediated decrements in mitochondrial gene transcription, expression, and translation.
These hypotheses will be tested in three groups of experiments, using a rat model of endotoxin-induced
sepsis. The purpose of Objective I is to fully characterize the specific physiologic derangements in the
mitochondria in sepsis; we will examine Krebs cycle enzyme activities, evaluate specific performance of
complexes within the electron transport chain, assess sarcomeric mitochondrial creatine kinase activity, and
perform a metabolic control analysis. Objective II will identify changes in the content and composition of
mitochondrial protein constituents (i.e. electron transport chain protein subunits, Krebs cycle enzymes,
creatine kinase) and compare the time course of these alterations with the development of physiologic
abnormalities determined in Objective I. Objective III will evaluate transcription, expression, and translation
of mitochondrial and nuclear genes encoding for mitochondrial proteins found to be depleted in Objective II.
In all studies, we will determine the role of free radical modulation of these sepsis-induced changes.
Our preliminary data provide the first evidence of substantial sepsis-associated oxidative modification
and depletion of mitochondrial protein subunits in Complexes I, III and IV, significant alterations in NADH
generation via Krebs cycle enzymes, major decreases in mitochondrial creatine kinase activity, and key free
radical-mediated changes in gene expression of mitochondrial proteins in sepsis. These data suggest that
the proposed experiments should provide important information regarding the pathogenesis of mitochondrial
dysfunction in sepsis.
Status | Finished |
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Effective start/end date | 6/1/01 → 5/31/08 |
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