Complex inhibitory effects of nitric oxide on autophagy

Sovan Sarkar, Viktor I Korolchuk, Maurizio Renna, Sara Imarisio, Angeleen Fleming, Andrea Williams, Moises Garcia-Arencibia, Claudia Rose, Shouqing Luo, Benjamin R Underwood, Guido Kroemer, Cahir J O'Kane, David C Rubinsztein

Research output: Contribution to journalArticlepeer-review

257 Citations (Scopus)


Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKKβ. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2-Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKKβ and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1-Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition.

Original languageEnglish
Pages (from-to)19-32
Number of pages14
JournalMolecular Cell
Issue number1
Publication statusPublished - 8 Jul 2011


  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy
  • Cell Line
  • Class III Phosphatidylinositol 3-Kinases
  • Enzyme Inhibitors
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Huntington Disease
  • I-kappa B Kinase
  • Membrane Proteins
  • Mice
  • Mitogen-Activated Protein Kinase 8
  • Multiprotein Complexes
  • NG-Nitroarginine Methyl Ester
  • Nerve Tissue Proteins
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nuclear Proteins
  • Phosphorylation
  • Protein Isoforms
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Rats
  • TOR Serine-Threonine Kinases
  • Tumor Suppressor Proteins


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