Protecting the Permeability Pore and Mitochondrial Biogenesis

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Book Section

© Novartis Foundation 2007. All rights reserved. Recent evidence links the pathogenesis of multiple organ dysfunction syndrome (MODS) in sepsis to mitochondrial damage. Our hypothesis is that cellular mechanisms maintaining mitochondrial function must be protected in order to prevent MODS. Recent animal experiments indicate that host defences which target and kill microbes, in part via reactive oxygen and nitrogen production, also injure mitochondria, thus activating mitochondrial cell death pathways. To limit such collateral damage, the cell up-regulates and imports into mitochondria several nuclear-encoded proteins for antioxidant defence and mitochondrial DNA (mtDNA) replication. Fully integrated responses lead to mitochondrial biogenesis, which may alter cellular phenotype to avoid mitochondrial permeability transition, apoptosis, or energy failure. Key to the cell's vulnerability to oxidant generation by the innate immune response is the mtDNA content. MtDNA depletion is opposed by oxidation-reduction (redox) signals that communicate the extent of mitochondrial damage to the nucleus. Molecular studies suggest that redox mechanisms activate two biogenic transcription factors, nuclear respiratory factors 1 and 2, which forestall a deterioration of oxidative phosphorylation during infection. Biogenic failure or an intrinsic biogenic arrest could hasten degradation of mitochondrial function and drive the cell to apoptosis or necrosis. By implication, novel protective strategies for biogenesis hold promise for the prevention of MODS.

Full Text

Duke Authors

Cited Authors

  • Piantadosi, CA; Carraway, MS; Haden, DW; Suliman, HB

Published Date

  • October 7, 2008

Volume / Issue

  • 280 /

Book Title

  • Sepsis: New Insights, New Therapies

Start / End Page

  • 266 - 276

International Standard Book Number 10 (ISBN-10)

  • 0470027983

International Standard Book Number 13 (ISBN-13)

  • 9780470027981

Digital Object Identifier (DOI)

  • 10.1002/9780470059593.ch18

Citation Source

  • Scopus