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Free Radic Biol Med. 2014 Feb;67:330-41. doi: 10.1016/j.freeradbiomed.2013.11.012. Epub 2013 Nov 22.

A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.

Author information

1
Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27834, USA.
2
Department of Physiology, East Carolina University, Greenville, NC 27834, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
3
MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
4
Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27834, USA; Department of Kinesiology, East Carolina University, Greenville, NC 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA.
5
Department of Pharmacology and Toxicology, East Carolina University, Greenville, NC 27834, USA; East Carolina Diabetes and Obesity Institute, East Carolina University, Greenville, NC 27834, USA. Electronic address: robidouxj@ecu.edu.

Abstract

Preadipocytes are periodically subjected to fatty acid (FA) concentrations that are potentially cytotoxic. We tested the hypothesis that prolonged exposure of preadipocytes of human origin to a physiologically relevant mix of FAs leads to mitochondrial inner membrane (MIM) permeabilization and ultimately to mitochondrial crisis. We found that exposure of preadipocytes to FAs led to progressive cyclosporin A-sensitive MIM permeabilization, which in turn caused a reduction in MIM potential, oxygen consumption, and ATP synthetic capacity and, ultimately, death. Additionally, we showed that FAs induce a transient increase in intramitochondrial reactive oxygen species (ROS) and lipid peroxide production, lasting roughly 30 and 120min for the ROS and lipid peroxides, respectively. MIM permeabilization and its deleterious consequences including mitochondrial crisis and cell death were prevented by treating the cells with the mitochondrial FA uptake inhibitor etomoxir, the mitochondrion-selective superoxide and lipid peroxide antioxidants MitoTempo and MitoQ, or the lipid peroxide and reactive carbonyl scavenger l-carnosine. FAs also promoted a delayed oxidative stress phase. However, the beneficial effects of etomoxir, MitoTempo, and l-carnosine were lost by delaying the treatment by 2h, suggesting that the initial phase was sufficient to prime the cells for the delayed MIM permeabilization and mitochondrial crisis. It also suggested that the second ROS production phase is a consequence of this loss in mitochondrial health. Altogether, our data suggest that approaches designed to diminish intramitochondrial ROS or lipid peroxide accumulation, as well as MIM permeabilization, are valid mechanism-based therapeutic avenues to prevent the loss in preadipocyte metabolic fitness associated with prolonged exposure to elevated FA levels.

KEYWORDS:

ATP; Bioenergetic; Fatty acids; Free radicals; H(2)O(2); Lipid peroxidation; Mitochondria; Mitochondrial inner membrane permeability; Mitochondrial inner membrane potential; Preadipocytes; Respiration; Superoxide

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