Logo image
Back
A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids
Journal article   Peer reviewed

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

Carlyle Rogers, Barbara Davis, P. Darrell Neufer, Michael P Murphy, Ethan J Anderson and Jacques Robidoux
Free radical biology & medicine, Vol.67, pp.330-341
02/2014
DOI: 10.1016/j.freeradbiomed.2013.11.012
PMCID: PMC3935619
PMID: 24269897

View Online

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. [Display omitted] •We studied the mitochondrial consequences of prolonged fatty acids in preadipocytes.•There were two phases of increased steady-state levels of ROS and lipid peroxidation.•The delayed phase occurred as a consequence of inner membrane permeabilization.•The initial phase primed the cells for delayed inner membrane permeabilization.•Mitochondrion-targeted antioxidants prevented these effects of fatty acids.
 Mitochondria Free radicals Preadipocytes Lipid peroxidation Mitochondrial inner membrane potential Superoxide Respiration H2O2 Fatty acids ATP Bioenergetic Mitochondrial inner membrane permeability

Details

Metrics

27 Record Views
16 Times Cited - Web of Science
Logo image