Cellular Senescence Induced by Malate-Aspartate Shuttle in Human Fibroblasts WI-38
Date Issued
2004
Date
2004
Author(s)
Teng, Chun-Hung
DOI
zh-TW
Abstract
Mitochondria, as cellular energy factory mediate producing energy and regulating metabolic pathway. However, mitochondrial dysfunction also affects the fate of cell, such as cellular senescence or apoptosis. Aminooxyacetic acid (AOA), a potent inhibitor of the mitochondrial malate-aspartate shuttle, causes cellular energy depletion by inhibiting the transfer of the NADH reducing potential produced by glycolysis to mitochondrion. In this study, we provide the evidence that AOA can also induce cellular senescence. By treating with 2.5 mM AOA, cellular senescence ratio began to increase at second day and up to 68.5% at sixth day. It is known that mitochondria dysfunction may result in AMPK activation or H2O2 generation. Both situations induced cellular senescence. In order to investigate AOA effect on cellular senescence has any relationship with the known pathways, cells were treated with 1 mM AICAR and 2.5 mM AOA simultaneously for six days. There is no additive effect in AOA-induced senescence ratio, and 100μM NAC(N-Acetyl-L-cysteine) which block H2O2 effect also can not prevent AOA effect on cellular senescence. AOA may influence the balance of NAD+/NADH between mitochondria and cytosol. By measuring total NAD+/NADH ratio, it shows no significant change. According to literature, during apoptosis process AIF released from mitochondria may be related to NAD+/NADH ratio. We did observe AIF released from mitochondria under 2.5 mM AOA treatment and it correlates to cellular senescence ratio.
Subjects
纖維母細胞WI-38
AIF
AOA
Type
other