Bcl-2 and tBid proteins counter-regulate mitochondrial potassium transport.
The mechanism of cytochrome c release from mitochondria in apoptosis remains obscure, although it is known to be regulated by bcl-2 family proteins. Here we describe a set of novel apoptotic phenomena--stimulation of the mitochondrial potassium uptake preceding cytochrome c release and regulation of such potassium uptake by bcl-2 family proteins. As a result of increased potassium uptake, mitochondria undergo moderate swelling sufficient to release cytochrome c. Overexpression of bcl-2 protein prevented the mitochondrial potassium uptake as well as cytochrome c release in apoptosis. Bcl-2 was found to upregulate the mitochondrial potassium efflux mechanism--the K/H exchanger. Specific activation of the mitochondrial K-uniporter led to cytochrome c release, which was inhibited by bcl-2. tBid had an opposite effect-it stimulated mitochondrial potassium uptake resulting in cytochrome c release. The described counter-regulation of mitochondrial potassium transport by bcl-2 and Bid suggests a novel view of a mechanism of cytochrome c release from mitochondria in apoptosis.
Eliseev
Roman A
RA
Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Salter
Jason D
JD
Gunter
Karlene K
KK
Gunter
Thomas E
TE
D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000502:physiology*; D006801:Humans; D017136:Ion Transport; D008928:Mitochondria / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011188:Potassium