Diaphragm Mitochondrial Alterations in Sepsis

  • Callahan, Leigh Ann (PI)
  • Supinski, Gerald (CoI)

Grants and Contracts Details


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.
Effective start/end date6/1/015/31/08


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.