Increased fuel delivery to mitochondria will generate substrate for mitochondrial respiration increasing the inner membrane potential (psidelta) thereby providing energy for ADP conversion to ATP. However, another consequence of increased psidelta is the generation of reactive oxygen leading to formation of superoxide and secondary generation of more detrimental free radicals. Hence, mitochondrial free radical formation may be one way in which increased fat delivery to non-adipose cells may be detrimental or induce """"""""lipotoxicity"""""""". On the other hand, non-oxidative metabolism of excess fat may also lead to lipotoxicity through accumulation of cellular fat and induction of lipid peroxidation both of which may contribute to cell dysfunction or apoptosis. There is evidence that mitochondria may adapt to increased fuel delivery through increased respiratory uncoupling. In fact, various physiologic states associated with increased circulating free fatty acids (FFAs) result in enhanced mitochondrial expression of uncoupling proteins capable of dissipating mitochondrial potential (deltapsi) theoretically protecting against both respiratory generation of reactive oxygen species (ROS) and accumulation of intracellular fat through non-oxidative pathways. There is also evidence for interactions between ROS and nitric oxide (NO) production. Thus respiratory uncoupling through effects on ROS could later an important specialized function of endothelial cells, i.e. NO production. Given these considerations, this proposal will test the following hypotheses: 1. Although suggested by our preliminary data the actual role of UCPs in catalyzing the proton leak in endothelial cell mitochondria is not proven. We hypothesize that this is the case. Further, we hypothesize that superoxide enhances the proton leak in BAE cells. 2. Endothelial cells exposed to high fat feeding as opposed to high glucose content or usual nutrient conditions will accumulate intracellular fat and generate increased reactive oxygen. However, this will be associated with enhanced respiratory uncoupling. 3. Enhanced respiratory uncoupling protects against ROS and excess non-oxidative fat metabolism. This is mediated by one or more UCP subtype. 4. Altered mitochondrial coupling and consequent changes in mitochondrial ROS formation alter endothelial cell generation of nitric oxide.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL073166-04
Application #
7120567
Study Section
Special Emphasis Panel (ZHL1-CSR-S (F1))
Program Officer
Barouch, Winifred
Project Start
2003-09-15
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$215,319
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Imai, Yumi; Fink, Brian D; Promes, Joseph A et al. (2018) Effect of a mitochondrial-targeted coenzyme Q analog on pancreatic ?-cell function and energetics in high fat fed obese mice. Pharmacol Res Perspect 6:e00393
Fink, Brian D; Guo, Deng Fu; Kulkarni, Chaitanya A et al. (2017) Metabolic effects of a mitochondrial-targeted coenzyme Q analog in high fat fed obese mice. Pharmacol Res Perspect 5:e00301
Suneja, Manish; Fox, Daniel K; Fink, Brian D et al. (2015) Evidence for metabolic aberrations in asymptomatic persons with type 2 diabetes after initiation of simvastatin therapy. Transl Res 166:176-87
Yu, Liping; Fink, Brian D; Sivitz, William I (2015) Simultaneous quantification of mitochondrial ATP and ROS production. Methods Mol Biol 1264:149-59
Fink, Brian D; Herlein, Judith A; Guo, Deng Fu et al. (2014) A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice. J Pharmacol Exp Ther 351:699-708
Yu, Liping; Fink, Brian D; Herlein, Judith A et al. (2014) Dietary fat, fatty acid saturation and mitochondrial bioenergetics. J Bioenerg Biomembr 46:33-44
Yu, Liping; Fink, Brian D; Herlein, Judith A et al. (2013) Mitochondrial function in diabetes: novel methodology and new insight. Diabetes 62:1833-42
Fink, Brian D; Herlein, Judith A; Yorek, Mark A et al. (2012) Bioenergetic effects of mitochondrial-targeted coenzyme Q analogs in endothelial cells. J Pharmacol Exp Ther 342:709-19
Fink, Brian D; Herlein, Judy A; O'Malley, Yunxia et al. (2012) Endothelial cell and platelet bioenergetics: effect of glucose and nutrient composition. PLoS One 7:e39430
Herlein, Judy A; Fink, Brian D; Sivitz, William I (2010) Superoxide production by mitochondria of insulin-sensitive tissues: mechanistic differences and effect of early diabetes. Metabolism 59:247-57

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