title: At the core of survival: autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury.
abstract: Ischemic cell injury leads to cell death. Three main morphologies have been described: apoptosis, cell death with autophagy and necrosis. Their inherent dynamic nature, a point of no return (PONR) and molecular overlap have been stressed. The relationship between a defined cell death type and the severity of injury remains unclear. The functional role of autophagy and its effects on cell death onset is largely unknown. In this study we report a differential induction of cell death, which is dependent on the severity and duration of an ischemic insult. We show that mild ischemia leads to the induction of autophagy and apoptosis, while moderate or severe ischemia induces both apoptotic and necrotic cell death without increased autophagy. The autophagic response during mild injury was associated with an ATP surge. Real-time imaging and Fluorescence Resonance Energy Transfer (FRET) revealed that increased autophagy delays the PONR of both apoptosis and necrosis significantly. Blocking autophagy shifted PONR to an earlier point in time. Our results suggest that autophagic activity directly alters intracellular metabolic parameters, responsible for maintaining mitochondrial membrane potential and cellular membrane integrity. A similar treatment also improved functional recovery in the perfused rat heart. Taken together, we demonstrate a novel finding: autophagy is implicated only in mild injury and positions the PONR in cell death.
authors.affiliation: Department of Physiological Sciences, Stellenbosch University, Mike de Vries Building, Merriman Street, Stellenbosch, 7600, South Africa. bloos@sun.ac.za
authors.forename: B
authors.initials: B
authors.lastname: Loos
authors.forename: S
authors.initials: S
authors.lastname: Genade
authors.forename: B
authors.initials: B
authors.lastname: Ellis
authors.forename: A
authors.initials: A
authors.lastname: Lochner
authors.forename: A-M
authors.initials: AM
authors.lastname: Engelbrecht
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015153:Blotting, Western; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005434:Flow Cytometry; D031541:Fluorescence Resonance Energy Transfer; D005455:Fluorescent Antibody Technique; D006321:Heart / Q000502:physiology; D007511:Ischemia / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009336:Necrosis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000255:Adenosine Triphosphate; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases