12(S)-hydroperoxyeicosatetraenoic acid (12-HETE) increases mitochondrial nitric oxide by increasing intramitochondrial calcium.
12(S)-hydroxyeicosatetraenoic acid (12-HETE) is one of the metabolites of arachidonic acid involved in pathological conditions associated with mitochondria and oxidative stress. The present study tested effects of 12-HETE on mitochondrial functions. In isolated rat heart mitochondria, 12-HETE increases intramitochondrial ionized calcium concentration that stimulates mitochondrial nitric oxide (NO) synthase (mtNOS) activity. mtNOS-derived NO causes mitochondrial dysfunctions by decreasing mitochondrial respiration and transmembrane potential. mtNOS-derived NO also produces peroxynitrite that induces release of cytochrome c and stimulates aggregation of mitochondria. Similarly, in HL-1 cardiac myocytes, 12-HETE increases intramitochondrial calcium and mitochondrial NO, and induces apoptosis. The present study suggests a novel mechanism for 12-HETE toxicity.
Nazarewicz
Rafal R
RR
Department of Surgery, Davis Heart and Lung Research Institute, Institute of Mitochondrial Biology, The Ohio State University, 460 West 12th Avenue, Columbus, OH 43210, USA.
Zenebe
Woineshet J
WJ
Parihar
Arti
A
Parihar
Mordhwaj S
MS
Vaccaro
Michael
M
Rink
Cameron
C
Sen
Chandan K
CK
Ghafourifar
Pedram
P
D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000008:administration & dosage*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D009569:Nitric Oxide; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D002118:Calcium