Paraoxonase 2 deficiency alters mitochondrial function and exacerbates the development of atherosclerosis.
Increased production of reactive oxygen species (ROS) as a result of decreased activities of mitochondrial electron transport chain (ETC) complexes plays a role in the development of many inflammatory diseases, including atherosclerosis. Our previous studies established that paraoxonase 2 (PON2) possesses antiatherogenic properties and is associated with lower ROS levels. The aim of the present study was to determine the mechanism by which PON2 modulates ROS production. In this report, we demonstrate that PON2-def mice on the hyperlipidemic apolipoprotein E(-/-) background (PON2-def/apolipoprotein E(-/-)) develop exacerbated atherosclerotic lesions with enhanced mitochondrial oxidative stress. We show that PON2 protein is localized to the inner mitochondrial membrane, where it is found associated with respiratory complex III. Employing surface-plasmon-resonance, we demonstrate that PON2 binds with high affinity to coenzyme Q(10), an important component of the ETC. Enhanced mitochondrial oxidative stress in PON2-def mice was accompanied by significantly reduced ETC complex I + III activities, oxygen consumption, and adenosine triphosphate levels in PON2-def mice. In contrast, overexpression of PON2 effectively protected mitochondria from antimycin- or oligomycin-mediated mitochondrial dysfunction. Our results illustrate that the antiatherogenic effects of PON2 are, in part, mediated by the role of PON2 in mitochondrial function.
Devarajan
Asokan
A
Department of Medicine, University of California, Los Angeles, California 90095, USA.
Bourquard
Noam
N
Hama
Susan
S
Navab
Mohamad
M
Grijalva
Victor R
VR
Morvardi
Susan
S
Clarke
Catherine F
CF
Vergnes
Laurent
L
Reue
Karen
K
Teiber
John F
JF
Reddy
Srinivasa T
ST
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism* / Q000503:physiopathology; D004036:Diet, Atherogenic; D004579:Electron Transport / Q000502:physiology; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism
D001057:Apolipoproteins E; D007527:Isoenzymes; D017382:Reactive Oxygen Species; D014451:Ubiquinone; D043303:Aryldialkylphosphatase; C024989:coenzyme Q10