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.
Formentini
Laura
L
Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Firenze, Italy.
Macchiarulo
Antonio
A
Cipriani
Giulia
G
Camaioni
Emidio
E
Rapizzi
Elena
E
Pellicciari
Roberto
R
Moroni
Flavio
F
Chiarugi
Alberto
A
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