Abstract:
RATIONALE:Activation of the mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) has been implicated in the mechanism of cardiac ischemic preconditioning, yet its molecular composition is unknown. OBJECTIVE:To use an unbiased proteomic analysis of the mitochondrial inner membrane to identify the mitochondrial K(+) channel underlying mitoK(ATP). METHODS AND RESULTS:Mass spectrometric analysis was used to identify KCNJ1(ROMK) in purified bovine heart mitochondrial inner membrane and ROMK mRNA was confirmed to be present in neonatal rat ventricular myocytes and adult hearts. ROMK2, a short form of the channel, is shown to contain an N-terminal mitochondrial targeting signal, and a full-length epitope-tagged ROMK2 colocalizes with mitochondrial ATP synthase β. The high-affinity ROMK toxin, tertiapin Q, inhibits mitoK(ATP) activity in isolated mitochondria and in digitonin-permeabilized cells. Moreover, short hairpin RNA-mediated knockdown of ROMK inhibits the ATP-sensitive, diazoxide-activated component of mitochondrial thallium uptake. Finally, the heart-derived cell line, H9C2, is protected from cell death stimuli by stable ROMK2 overexpression, whereas knockdown of the native ROMK exacerbates cell death. CONCLUSIONS:The findings support ROMK as the pore-forming subunit of the cytoprotective mitoK(ATP) channel.
journal_name
Circ Resjournal_title
Circulation researchauthors
Foster DB,Ho AS,Rucker J,Garlid AO,Chen L,Sidor A,Garlid KD,O'Rourke Bdoi
10.1161/CIRCRESAHA.112.266445subject
Has Abstractpub_date
2012-08-03 00:00:00pages
446-54issue
4eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.112.266445journal_volume
111pub_type
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