Poly(ADP-ribose) catabolism triggers AMP-dependent mitochondrial energy failure.
Upon massive DNA damage, hyperactivation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP)-1 causes severe depletion of intracellular NAD and ATP pools as well as mitochondrial dysfunction. Thus far, the molecular mechanisms contributing to PARP-1-dependent impairment of mitochondrial functioning have not been identified. We found that degradation of the PARP-1 product poly(ADP-ribose) through the concerted actions of poly(ADP-ribose) glycohydrolase and NUDIX (nucleoside diphosphate-X) hydrolases leads to accumulation of AMP. The latter, in turn, inhibits the ADP/ATP translocator, prompting mitochondrial energy failure. For the first time, our findings identify NUDIX hydrolases as key enzymes involved in energy derangement during PARP-1 hyperactivity. Also, these data disclose unanticipated AMP-dependent impairment of mitochondrial exchange of adenine nucleotides, which can be of relevance to organelle functioning and disease pathogenesis.
Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Firenze, Italy.
Laura
L
Formentini
Antonio
A
Macchiarulo
Giulia
G
Cipriani
Emidio
E
Camaioni
Elena
E
Rapizzi
Roberto
R
Pellicciari
Flavio
F
Moroni
Alberto
A
Chiarugi
D000244:Adenosine Diphosphate / Q000378:metabolism; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D015153:Blotting, Western; D004734:Energy Metabolism; D006026:Glycoside Hydrolases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D008928:Mitochondria / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011755:Pyrophosphatases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000096964:Nudix Hydrolases
D000244:Adenosine Diphosphate; D000246:Adenosine Diphosphate Ribose; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D006026:Glycoside Hydrolases; D011065:Poly(ADP-ribose) Polymerases; D011755:Pyrophosphatases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000096964:Nudix Hydrolases; C022407:poly ADP-ribose glycohydrolase