Protecting the permeability pore and mitochondrial biogenesis.
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.
Piantadosi
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Box 3315, Room 0570 DHS, Duke University Medical Center, Durham, NC 27710, USA.
Carraway
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Haden
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Suliman
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D000818:Animals; D002463:Cell Membrane Permeability; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D018805:Sepsis / Q000473:pathology*
D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species