cAMP-dependent protein kinase regulates the mitochondrial import of the nuclear encoded NDUFS4 subunit of complex I

Cell Signal. 2008 May;20(5):989-97. doi: 10.1016/j.cellsig.2008.01.017. Epub 2008 Jan 31.


The subunits of complex I encoded by the mammalian nuclear genes NDUFS4 (AQDQ protein) and NDUFB11 (ESSS protein) contain serine/threonine consensus phosphorylation sequences (CPS) in their presequence, the first also in the C-terminus. We have studied the impact of PKA mediated phosphorylation on the mitochondrial import of in vitro and in vivo synthesized NDUFS4 protein. The intramitochondrial accumulation of the mature form of in vitro synthesized NDUFS4 protein, but not that of ESSS protein, was promoted by PKA and depressed by alkaline phosphatase (AP). In HeLa cells, control or transfected with the NDUFS4 cDNA construct, the mitochondrial level of mature NDUFS4 protein was promoted by 8-Br-cAMP and depressed by H89. Ser173Ala mutagenesis in the C-terminus CPS abolished the appearance in mitochondria of the mature form of NDUFS4 protein. The promoting effect of PKA on the mitochondrial accumulation of mature NDUFS4 protein appears to be due to inhibition of its retrograde diffusion into the cytosol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Alkaline Phosphatase / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Biological Transport, Active / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Electron Transport Complex I / genetics
  • Electron Transport Complex I / metabolism
  • HeLa Cells
  • Humans
  • In Vitro Techniques
  • Isoquinolines / pharmacology
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • NADH Dehydrogenase / genetics
  • NADH Dehydrogenase / metabolism*
  • Protein Subunits
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sulfonamides / pharmacology


  • Isoquinolines
  • NDUFB11 protein, human
  • Protein Subunits
  • Recombinant Proteins
  • Sulfonamides
  • 8-Bromo Cyclic Adenosine Monophosphate
  • NADH Dehydrogenase
  • Cyclic AMP-Dependent Protein Kinases
  • Alkaline Phosphatase
  • Electron Transport Complex I
  • NDUFS4 protein, human
  • N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide