Helicobacter pylori vacuolating cytotoxin A (VacA) engages the mitochondrial fission machinery to induce host cell death

Abstract

A number of pathogenic bacteria target mitochondria to modulate the host's apoptotic machinery. Studies here revealed that infection with the human gastric pathogen Helicobacter pylori disrupts the morphological dynamics of mitochondria as a mechanism to induce host cell death. The vacuolating cytotoxin A (VacA) is both essential and sufficient for inducing mitochondrial network fragmentation through the mitochondrial recruitment and activation of dynamin-related protein 1 (Drp1), which is a critical regulator of mitochondrial fission within cells. Inhibition of Drp1-induced mitochondrial fission within VacA-intoxicated cells inhibited the activation of the proapoptotic Bcl-2-associated X (Bax) protein, permeabilization of the mitochondrial outer membrane, and cell death. Our data reveal a heretofore unrecognized strategy by which a pathogenic microbe engages the host's apoptotic machinery.cytochrome c | mitochondrial dynamics | gastric cancer | gastric ulcer | toxin

The Makes Caterpillars Floppy (MCF)-Like Domain of Vibrio vulnificus Induces Mitochondrion-Mediated Apoptosis

“…cifically target mitochondria by manipulating mitochondrial dynamics, including VacA from Helicobacter pylori (43) and the T3SS effector VopE from V. cholerae (44). However, Western blotting of cytosolic and membrane fractionation of HeLa cells transfected to express MCF Vv did not reveal significant partitioning of MCF Vv in the membrane (data not shown).…”

The Intermediate Region of Helicobacter pylori VacA Is a Determinant of Toxin Potency in a Jurkat T Cell Assay

“…A current model proposes that VacA monomers interact with the plasma membrane and subsequently oligomerize, which allows the formation of VacA pores in cell membranes (9). VacA causes a wide range of alterations in human gastric cells (9), including the formation of large cytoplasmic vacuoles (11,40), permeabilization of the plasma membrane (65), reduction of mitochondrial transmembrane potential (19,24,26,74), mitochondrial cytochrome c release (19,24,26,74), mitochondrial fragmentation (35), activation of mitogen-activated protein kinases (49), induction of autophagy (67), and cell death (13,26,35,53). Most of these effects (but not all) are dependent on membrane channel formation by VacA (30,34,46,71).…”

Role of Connexin 43 in Helicobacter pylori VacA-Induced Cell Death

“…Effects of VacA on mitochondria include reduction in mitochondrial transmembrane potential, cytochrome c release, and mitochondrial network fragmentation (30,(38)(39)(40)(41)(42)(43), which can lead to poly(ADPribose) polymerase (PARP) cleavage, reduction of cellular ATP content, and impaired cell cycle progression (9,35,(41)(42)(43). The proapoptotic factors BAX and BAK, as well as dynamin-related protein 1 (Drp1), have roles in VacA-mediated cell death (31, 42,44).…”

“…The proapoptotic factors BAX and BAK, as well as dynamin-related protein 1 (Drp1), have roles in VacA-mediated cell death (31, 42,44). VacA can cause cell death in several cell lines, including HeLa (30, 38, 39,45), AGS (20,36,37,41,46), and AZ-521 cells (25,35,42,44,47), but among these cell types, AZ-521 cells are the most susceptible to VacA-mediated killing (35). The molecular mechanisms underlying this enhanced susceptibility of AZ-521 cells are not understood.…”

“…Effects of VacA on mitochondria include reduction in mitochondrial transmembrane potential, cytochrome c release, and mitochondrial network fragmentation (30,(38)(39)(40)(41)(42)(43), which can lead to poly(ADPribose) polymerase (PARP) cleavage, reduction of cellular ATP content, and impaired cell cycle progression (9,35,(41)(42)(43). The proapoptotic factors BAX and BAK, as well as dynamin-related protein 1 (Drp1), have roles in VacA-mediated cell death (31, 42,44). VacA can cause cell death in several cell lines, including HeLa (30, 38, 39,45), AGS (20,36,37,41,46), and AZ-521 cells (25,35,42,44,47), but among these cell types, AZ-521 cells are the most susceptible to VacA-mediated killing (35).…”