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

TitleA transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.
Publication TypeJournal Article
Year of Publication2014
AuthorsRogers, C, Davis, B, P Neufer, D, Murphy, MP, Anderson, EJ, Robidoux, J
JournalFree Radic Biol Med
Volume67
Pagination330-41
Date Published2014 Feb
ISSN1873-4596
KeywordsAdenosine Triphosphate, Adipocytes, Carnosine, Cell Death, Cell Differentiation, Cell Line, Transformed, Cyclosporine, Epoxy Compounds, Fatty Acids, Gene Expression, Humans, Lipid Peroxidation, Membrane Potential, Mitochondrial, Mitochondria, Mitochondrial Membranes, Organophosphorus Compounds, Oxidative Stress, Permeability, Piperidines, Reactive Oxygen Species, Superoxides, Ubiquinone
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.

DOI10.1016/j.freeradbiomed.2013.11.012
Alternate JournalFree Radic. Biol. Med.
Citation Key10.1016/j.freeradbiomed.2013.11.012
PubMed ID24269897
PubMed Central IDPMC3935619
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom
R01 DK074825 / DK / NIDDK NIH HHS / United States
R01DK096907 / DK / NIDDK NIH HHS / United States