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Related Experiment Videos

Nuclear poly(ADP-ribose) polymerase-1 rapidly triggers mitochondrial dysfunction.

Giulia Cipriani1, Elena Rapizzi, Alfredo Vannacci

  • 1Department of Pharmacology, University of Florence, 50139 Florence, Italy.

The Journal of Biological Chemistry
|March 8, 2005
PubMed
Summary

Poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation triggers rapid cell death by depleting cellular energy. PARP-1 inhibitors prevent this energy loss and cell death, highlighting PARP-1

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Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in DNA repair.
  • PARP-1 hyperactivation can lead to cell death.
  • The precise mechanisms and time course of cell death following PARP-1 hyperactivation are not fully understood.

Purpose of the Study:

  • To investigate the time course and mechanisms of cell death induced by PARP-1 hyperactivation.
  • To elucidate the role of PARP-1 in cellular energy metabolism and mitochondrial function during cell death.
  • To explore the cross-talk between the nucleus and mitochondria in PARP-1-dependent cell death.

Main Methods:

  • HeLa cells were treated with the DNA alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine.

Related Experiment Videos

  • PARP-1 activity, cellular NAD(H) and ATP levels, mitochondrial membrane potential, and superoxide production were measured.
  • Apoptosis-inducing factor and cytochrome c release were assessed.
  • Immunocytochemistry and luciferase transfection were used to determine the localization of PARP-1 and poly(ADP-ribose).

    • Main Results:

    • N-methyl-N'-nitro-N-nitrosoguanidine treatment activated PARP-1, causing rapid depletion of cellular NAD(H) and ATP, followed by cell death.
    • PARP-1 inhibitors prevented nucleotide depletion and cell death.
    • Early PARP-1 activation led to increased mitochondrial membrane potential and superoxide production, suggesting mitochondrial state 4 respiration.
    • Mitochondrial membrane potential collapsed later, with release of apoptosis-inducing factor and cytochrome c.
    • ATP levels decreased first in mitochondria and then in the cytoplasm.
    • PARP-1 inhibitors rescued cytoplasmic ATP levels but not NAD(H) levels.
    • Glycolysis was crucial for energy recovery, while mitochondria initially consumed and later produced ATP after PARP-1 inhibition.

    Conclusions:

    • PARP-1 hyperactivation rapidly depletes cellular energy, leading to cell death.
    • PARP-1 activation induces significant changes in mitochondrial function, including altered respiration and potential collapse.
    • There is rapid nucleus-mitochondria cross-talk involved in PARP-1-dependent cell death.
    • PARP-1 inhibitors can rescue cellular ATP levels and prevent cell death, suggesting therapeutic potential.