Document Detail


Coenzyme depletion by members of the aerolysin family of pore-forming toxins leads to diminished ATP levels and cell death.
MedLine Citation:
PMID:  22688384     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent studies demonstrated that a variety of bacterial pore-forming toxins induce cell death through a process of programmed necrosis characterized by the rapid depletion of cellular ATP. However, events leading to the necrosis and depletion of ATP are not thoroughly understood. We demonstrate that ATP-depletion induced by two pore-forming toxins, the Clostridium perfringens epsilon-toxin and the Aeromonas hydrophila aerolysin toxin, is associated with decreased mitochondrial membrane potential and opening of the mitochondrial permeability transition pore. To gain further insight into the toxin-induced metabolic changes contributing to necrosis and depletion of ATP, we analyzed the biochemical profiles of 251 distinct compounds by GC/MS or LC/MS/MS following exposure of a human kidney cell line to the epsilon-toxin. As expected, numerous biochemicals were seen to increase or decrease in response to epsilon-toxin. However, the pattern of these changes was consistent with the toxin-induced disruption of major energy-producing pathways in the cell including disruptions to the beta-oxidation of lipids. In particular, treatment with epsilon-toxin led to decreased levels of key coenzymes required for energy production including carnitine, NAD (and NADH), and coenzyme A. Independent biochemical assays confirmed that epsilon-toxin and aerolysin induced the rapid decrease of these coenzymes or their synthetic precursors. Incubation of cells with NADH or carnitine-enriched medium helped protect cells from toxin-induced ATP depletion and cell death. Collectively, these results demonstrate that members of the aerolysin family of pore-forming toxins lead to decreased levels of essential coenzymes required for energy production. The resulting loss of energy substrates is expected to contribute to dissipation of the mitochondrial membrane potential, opening of the mitochondrial permeability transition pore, and ultimately cell death.
Authors:
Christine M Fennessey; Susan E Ivie; Mark S McClain
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-06-11
Journal Detail:
Title:  Molecular bioSystems     Volume:  8     ISSN:  1742-2051     ISO Abbreviation:  Mol Biosyst     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-07-04     Completed Date:  2012-10-31     Revised Date:  2013-09-04    
Medline Journal Info:
Nlm Unique ID:  101251620     Medline TA:  Mol Biosyst     Country:  England    
Other Details:
Languages:  eng     Pagination:  2097-105     Citation Subset:  IM    
Affiliation:
Division of Infectious Disease, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Aeromonas hydrophila / chemistry
Bacterial Toxins / pharmacology*
Carnitine / metabolism
Cell Death / drug effects
Cell Line
Coenzyme A / metabolism
Humans
NAD / metabolism
Pore Forming Cytotoxic Proteins / pharmacology*
Grant Support
ID/Acronym/Agency:
R01 AI079123/AI/NIAID NIH HHS; R01-AI079123/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Bacterial Toxins; 0/Clostridium perfringens epsilon-toxin; 0/Pore Forming Cytotoxic Proteins; 53-84-9/NAD; 53126-24-2/aerolysin; 541-15-1/Carnitine; 56-65-5/Adenosine Triphosphate; 85-61-0/Coenzyme A
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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