title: Glucose deprivation converts poly(ADP-ribose) polymerase-1 hyperactivation into a transient energy-producing process.
abstract: Massive poly(ADP-ribose) formation by poly(ADP-ribose) polymerase-1 (PARP-1) triggers NAD depletion and cell death. These events have been invariantly related to cellular energy failure due to ATP shortage. The latter occurs because of both ATP consumption for NAD resynthesis and impairment of mitochondrial ATP formation caused by an increase of the AMP/ADP ratio. ATP depletion is therefore thought to be an inevitable consequence of NAD loss and a hallmark of PARP-1 activation. Here, we challenge this scenario by showing that PARP-1 hyperactivation in cells cultured in the absence of glucose (Glu(-) cells) is followed by NAD depletion and an unexpected PARP-1 activity-dependent ATP increase. We found increased ADP content in resting Glu(-) cells, a condition that counteracts the increase of the AMP/ADP ratio during hyperpoly(ADP-ribosyl)ation and preserves mitochondrial coupling. We also show that the increase of ATP in Glu(-) cells is due to adenylate kinase activity, transforming AMP into ADP which, in turn, is converted into ATP by coupled mitochondria. Interestingly, PARP-1-dependent mitochondrial release of apoptosis-inducing factor (AIF) and cytochrome complex (Cyt c) is reduced in Glu(-) cells, even though cell death eventually occurs. Overall, the present study identifies basal ADP content and adenylate kinase as key determinants of bioenergetics during PARP-1 hyperactivation and unequivocally demonstrates that ATP loss is not metabolically related to NAD depletion.
authors.affiliation: From the Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, 50139 Florence, Italy and.
authors.forename: Daniela
authors.initials: D
authors.lastname: Buonvicino
authors.forename: Laura
authors.initials: L
authors.lastname: Formentini
authors.forename: Giulia
authors.initials: G
authors.lastname: Cipriani
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
mesh_terms: D016475:3T3 Cells; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*
chemical_list: D051033:Apoptosis Inducing Factor; D009243:NAD; D011064:Poly Adenosine Diphosphate Ribose; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D000263:Adenylate Kinase; D005947:Glucose
keywords: ADP; AMP; ATP; Adenine Nucleotides; Adenylate Kinases; Glucose; Mitochondria; Poly(ADP-ribose) Polymerase-1