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Mitochondria-associated endoplasmic reticulum membranes dysfunction contributes to PARP-1-dependent cell death under

Yuting Yang1, Jihong Wu1,2, Wei Lu1

  • 1Department of Ophthalmology & Visual Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Journal of Biochemical and Molecular Toxicology
|January 14, 2023
PubMed

Insights

Persistent poly (ADP-ribose) polymerase 1 (PARP-1) activation causes cell death. A PARP-1 inhibitor, olaparib, protected retinal cells from hydrogen peroxide (H2O2)-induced death and mitigated mitochondria-associated ER membrane (MAM) dysregulation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Persistent activation of poly (ADP-ribose) polymerase 1 (PARP-1) is detrimental, leading to cell death.
  • Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are crucial for cellular processes like autophagy and mitochondrial dynamics.
  • Oxidative stress, induced by hydrogen peroxide (H2O2), disrupts cellular homeostasis and can lead to MAM dysregulation.

Purpose of the Study:

  • To investigate the protective effects of a PARP-1 inhibitor against H2O2-induced persistent PARP-1 activation and MAM dysregulation.
  • To explore the role of MAMs and mitofusin-2 (MFN2) in H2O2-induced cell death and oxidative stress.

Main Methods:

  • Utilized a PARP-1 inhibitor (olaparib) and other inhibitors (necrostatin-1, Z-VAD-FMK) to treat retinal precursor cells exposed to H2O2.
  • Assessed cell viability, MAM integrity (VDAC1/ITPR3 interactions), mitochondrial membrane potential, and autophagy.
  • Investigated the effects of MFN2 knockdown and overexpression on MAMs and mitochondrial function under normal and oxidative conditions.

Main Results:

  • Olaparib and necrostatin-1 protected retinal precursor cells from H2O2-induced death, unlike a pan-caspase inhibitor.
  • Olaparib mitigated H2O2-induced MAM dysregulation, evidenced by reduced VDAC1/ITPR3 interactions and preserved mitochondrial membrane potential.
  • H2O2 induced autophagy, which was inhibited by olaparib; inhibiting autophagic flux exacerbated MAM signaling. MFN2 knockdown worsened MAM and mitochondrial dysfunction, while MFN2 overexpression enhanced H2O2-induced MAM signaling.

Conclusions:

  • MAMs may serve as a membrane source for oxidative stress-associated autophagy.
  • MAM dysregulation contributes to PARP-1-dependent cell death under oxidative stress.
  • Further research is needed to clarify the complex interplay between MFN2, MAM integrity, and mitochondrial function in oxidative stress.
Keywords:
MAMMFN2OlaparibPARP-1hydrogen peroxide

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