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Mitochondrial c-Src regulates cell survival through phosphorylation of respiratory chain components

Masato Ogura1, Junko Yamaki, Miwako K Homma

  • 1Department of Biomolecular Science, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan.

The Biochemical Journal
|July 25, 2012
PubMed

Insights

Mitochondrial c-Src kinase phosphorylates key respiratory proteins, impacting cellular respiration and viability. This phosphorylation is crucial for maintaining mitochondrial function and overall cell survival.

Area of Science:

  • Mitochondrial biology
  • Cellular signaling
  • Biochemistry

Background:

  • Mitochondrial protein tyrosine phosphorylation regulates mitochondrial functions.
  • The role of Src family kinases in mitochondria is not fully understood.

Purpose of the Study:

  • Identify novel mitochondrial substrates of c-Src.
  • Investigate the function of these substrates in regulating oxidative phosphorylation and cell viability.

Main Methods:

  • Utilized Src family kinase inhibitor PP2 and kinase-dead c-Src.
  • Performed phosphorylation-site analysis to identify c-Src targets.
  • Conducted in vivo assays using phosphorylation-defective mutants.
  • Assessed enzyme activity, electron transfer, reactive oxygen species production, and cell viability.

Main Results:

  • Identified NDUFV2 (NADH dehydrogenase [ubiquinone] flavoprotein 2) and SDHA (succinate dehydrogenase A) as mitochondrial c-Src substrates.
  • NDUFV2 phosphorylation by c-Src is required for NADH dehydrogenase activity, affecting respiration and ATP content.
  • SDHA phosphorylation by c-Src perturbs electron transfer and induces reactive oxygen species.
  • Expression of phosphorylation-defective mutants leads to loss of cell viability in T98G cells and primary neurons.

Conclusions:

  • Mitochondrial c-Src regulates oxidative phosphorylation by phosphorylating respiratory components.
  • c-Src activity is essential for mitochondrial function and cell viability.

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