ATP depletion via mitochondrial F 1F 0 complex by lethal factor is an early event in B. anthracis-induced sudden cell death

Mitchell W. Woodberry, Leopoldo Aguilera-Aguirre, Attila Bacsi, Ashok Chopra, Alexander Kurosky, Johnny Peterson, Istvan Boldogh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Bacillus anthracis' primary virulence factor is a tripartite anthrax toxin consisting of edema factor (EF), lethal factor (LF) and protective antigen (PA). In complex with PA, EF and LF are internalized via receptor-mediated endocytosis. EF is a calmodulindependent adenylate cyclase that induces tissue edema. LF is a zinc-metalloprotease that cleaves members of mitogen-activated protein kinase kinases. Lethal toxin (LT: PA plus LF)-induced death of macrophages is primarily attributed to expression of the sensitive Nalp1b allele, inflammasome formation and activation of caspase-1, but early events that initiate these processes are unknown. Here we provide evidence that an early essential event in pyroptosis of alveolar macrophages is LF-mediated depletion of cellular ATP. The underlying mechanism involves interaction of LF with F 1F 0-complex gamma and beta subunits leading to increased ATPase activity in mitochondria. In support, mitochondrial DNA-depleted MH-S cells have decreased F 1F 0 ATPase activity due to the lack of F 06 and F 08 polypeptides and show increased resistance to LT. We conclude that ATP depletion is an important early event in LT-induced sudden cell death and its prevention increases survival of toxin-sensitive cells.

Original languageEnglish (US)
Pages (from-to)25-39
Number of pages15
JournalJournal of Cell Death
Volume2009
StatePublished - 2009

Fingerprint

Cell death
Sudden Death
Cell Death
Adenosine Triphosphate
Antigens
Adenosine Triphosphatases
Inflammasomes
Bacillus anthracis
Caspase 1
Mitochondria
Proton-Translocating ATPases
Macrophages
Mitogen-Activated Protein Kinase Kinases
Alveolar Macrophages
Metalloproteases
Virulence Factors
Bacilli
Endocytosis
Mitochondrial DNA
Adenylyl Cyclases

Keywords

  • Anthrax lethal factor
  • Atpase
  • F1F0
  • Mitochondria
  • Pyroptosis

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

Cite this

ATP depletion via mitochondrial F 1F 0 complex by lethal factor is an early event in B. anthracis-induced sudden cell death. / Woodberry, Mitchell W.; Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Chopra, Ashok; Kurosky, Alexander; Peterson, Johnny; Boldogh, Istvan.

In: Journal of Cell Death, Vol. 2009, 2009, p. 25-39.

Research output: Contribution to journalArticle

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T1 - ATP depletion via mitochondrial F 1F 0 complex by lethal factor is an early event in B. anthracis-induced sudden cell death

AU - Woodberry, Mitchell W.

AU - Aguilera-Aguirre, Leopoldo

AU - Bacsi, Attila

AU - Chopra, Ashok

AU - Kurosky, Alexander

AU - Peterson, Johnny

AU - Boldogh, Istvan

PY - 2009

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AB - Bacillus anthracis' primary virulence factor is a tripartite anthrax toxin consisting of edema factor (EF), lethal factor (LF) and protective antigen (PA). In complex with PA, EF and LF are internalized via receptor-mediated endocytosis. EF is a calmodulindependent adenylate cyclase that induces tissue edema. LF is a zinc-metalloprotease that cleaves members of mitogen-activated protein kinase kinases. Lethal toxin (LT: PA plus LF)-induced death of macrophages is primarily attributed to expression of the sensitive Nalp1b allele, inflammasome formation and activation of caspase-1, but early events that initiate these processes are unknown. Here we provide evidence that an early essential event in pyroptosis of alveolar macrophages is LF-mediated depletion of cellular ATP. The underlying mechanism involves interaction of LF with F 1F 0-complex gamma and beta subunits leading to increased ATPase activity in mitochondria. In support, mitochondrial DNA-depleted MH-S cells have decreased F 1F 0 ATPase activity due to the lack of F 06 and F 08 polypeptides and show increased resistance to LT. We conclude that ATP depletion is an important early event in LT-induced sudden cell death and its prevention increases survival of toxin-sensitive cells.

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