A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.
A transient increase in lipid peroxidation primes preadipocytes for delayed mitochondrial inner membrane permeabilization and ATP depletion during prolonged exposure to fatty acids.
复制标题
DOI：
10.1016/j.freeradbiomed.2013.11.012
复制
发表时间：
2014-02
影响因子：
7.4
通讯作者：
Robidoux, Jacques
中科院分区：
文献类型：
--
作者：
Rogers, Carlyle;Davis, Barbara;Neufer, P. Darrell;Murphy, Michael P.;Anderson, Ethan J.;Robidoux, Jacques
关键词：
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 reduction in MIM potential (ΔΨM), oxygen consumption, ATP synthetic capacity, and ultimately death. Additionally, we showed that FAs induce a transient increase in intramitochondrial ROS and lipid peroxide production lasting roughly 30 and 120 minutes 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, since the beneficial effects of Etomoxir, MitoTempo and L-carnosine were lost by delaying the treatment by 2 hours, it suggested 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.
登录
查看更多内容
影响因子：
7.7
作者：
Curtis JM;Grimsrud PA;Wright WS;Xu X;Foncea RE;Graham DW;Brestoff JR;Wiczer BM;Ilkayeva O;Cianflone K;Muoio DE;Arriaga EA;Bernlohr DA
通讯作者：
Bernlohr DA
影响因子：
--
作者：
HALLGREN, P;SJOSTROM, L;OLBE, L
通讯作者：
OLBE, L
影响因子：
9.8
作者：
FRAYN, KN;COPPACK, SW;EVANS, RD
通讯作者：
EVANS, RD
影响因子：
9.3
作者：
Frohnert, Brigitte I.;Bernlohr, David A.
通讯作者：
Bernlohr, David A.
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell