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α7 nicotinic acetylcholine receptors control cytochrome c release from isolated mitochondria through kinase-mediated

Galyna Gergalova1, Olena Lykhmus1, Sergiy Komisarenko1

  • 1Palladin Institute of Biochemistry, 9, Leontovicha Str., Kyiv 01601, Ukraine.

The International Journal of Biochemistry & Cell Biology
|January 14, 2014
PubMed

Insights

Mitochondrial alpha7 nicotinic receptors regulate cell death pathways by influencing key protein kinases. These receptors control apoptosis and superoxide release via an ion-independent mechanism involving the PI3K/Akt pathway.

Area of Science:

  • Mitochondrial biology
  • Cell signaling
  • Neuroscience

Background:

  • Nicotinic acetylcholine receptors (nAChRs), particularly the alpha7 subtype (α7), are implicated in cellular processes beyond neuronal function.
  • Previous research identified α7 nAChRs on the outer mitochondrial membrane, regulating apoptosis.
  • The precise signaling mechanisms of mitochondrial α7 nAChRs remain incompletely understood.

Purpose of the Study:

  • To investigate the role of mitochondrial α7 nAChRs in regulating intramitochondrial protein kinases.
  • To elucidate the signaling pathways affected by mitochondrial α7 nAChRs during apoptotic events.
  • To determine the mechanism by which α7 nAChRs modulate mitochondrial function.

Main Methods:

  • Isolated mouse liver mitochondria were used to study the effects of α7 nAChR agonists and antagonists.
  • Cytochrome c release was measured as an indicator of apoptosis.
  • Protein phosphorylation states (e.g., Akt Ser 473) were assessed.
  • Superoxide release was quantified using a medium alkalization assay.

Main Results:

  • The α7 nAChR agonist PNU 282987 prevented wortmannin-induced cytochrome c release and restored Akt phosphorylation.
  • PNU 282987's effects mimicked those of inhibitors targeting calcium-calmodulin-dependent kinase II, Src kinases, and protein kinase C.
  • Both α7 nAChR antagonists and antibodies attenuated cytochrome c release.
  • Acetylcholine and an α7 nAChR antagonist inhibited mitochondrial superoxide release.

Conclusions:

  • Mitochondrial α7 nAChRs regulate the mitochondrial permeability transition pore.
  • This regulation occurs via an ion-independent mechanism involving the activation of the intramitochondrial PI3K/Akt pathway.
  • α7 nAChRs also inhibit calcium-calmodulin-dependent and Src-kinase-dependent signaling pathways within mitochondria.
Keywords:
Cytochrome cMitochondriaNicotinic acetylcholine receptorProtein kinasesSuperoxide

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