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Complex I and the cAMP cascade in human physiopathology

S Papa1, S Scacco, A M Sardanelli

  • 1Department of Medical Biochemistry and Biology, University of Bari, Italy. papabchm@cimedoc.uniba.it

Bioscience Reports
|November 7, 2002
PubMed

Insights

Mitochondrial cAMP-dependent protein kinase (PKA) phosphorylates Complex I, enhancing respiratory activity. Mutations in the NDUFS4 gene linked to Complex I deficiency cause fatal neurological disorders.

Area of Science:

  • Mitochondrial biochemistry
  • Cellular respiration
  • Molecular genetics

Background:

  • Mitochondria contain cAMP-dependent protein kinase (PKA) that phosphorylates proteins on the matrix side of the inner membrane.
  • Complex I of the respiratory chain includes an 18 kDa subunit (encoded by NDUFS4) that is a substrate for mitochondrial PKA.
  • Mitochondria possess a Ca(2+)-inhibited phosphatase that dephosphorylates this 18 kDa subunit.

Purpose of the Study:

  • To investigate the role of cAMP-dependent phosphorylation of the 18 kDa subunit of Complex I in regulating mitochondrial respiratory activity.
  • To explore the functional consequences of NDUFS4 gene mutations associated with Complex I deficiency.

Main Methods:

  • Studies were conducted using fibroblast and myoblast cell cultures.
  • Assessed the impact of cAMP-dependent phosphorylation on Complex I activity and overall respiratory function with NAD-linked substrates.

Main Results:

  • cAMP-dependent phosphorylation of the 18 kDa protein was associated with increased Complex I activity.
  • This phosphorylation event correlated with enhanced overall respiratory activity when using NAD-linked substrates.
  • Mutations in the human NDUFS4 gene, when homozygous, lead to Complex I deficiency and a fatal neurological syndrome.

Conclusions:

  • Mitochondrial PKA-mediated phosphorylation of the NDUFS4-encoded 18 kDa subunit is a regulatory mechanism for Complex I and cellular respiration.
  • Dysfunction of this regulatory pathway, as seen in NDUFS4 mutations, can result in severe mitochondrial disease and neurological impairment.

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