We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production. CK666 treatment causes rapid mitochondrial actin loss and a drop in ATP in NDUFS4 knock-out cells. Two situations causing chronic reductions in mitochondrial ATP production, mitochondrial DNA depletion and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent perimitochondrial actin filaments similar to ADA. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium–calcium exchanger (NCLX) inhibitor CGP37157 inhibits both ADA and the glycolytic increase within 5 min, supporting ADA’s role in glycolytic stimulation. ADA-inducing treatments include CCCP, antimycin, rotenone, oligomycin, and hypoxia. In this study, we show evidence suggesting that ADA is linked to rapid glycolytic activation upon mitochondrial damage in multiple cells, including mouse embryonic fibroblasts and effector CD8 + T lymphocytes. The consequences of ADA are not understood. One rapid response is perimitochondrial actin polymerization, termed acute damage-induced actin (ADA). Mitochondrial damage represents a dramatic change in cellular homeostasis.
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