Biphasic Autophagy: A Solution to Cigarette Smoke-Induced Autophagy Conundrum - Abstract
Cigarette smoke-induced protein accumulation and aggresome formation is a major pathological hallmark of COPD disease. Aggresome formation results from a defect in autophagy. To understand the mechanism of cigarette smoke-induced autophagy defect, the current study examined autophagy kinetics and the status of mTOR and AMPK proteins of cigarette smoke extract (CSE)- treated A549 cells. The result showed that CSE-induced autophagy is biphasic. At the beginning of the first phase, phospho-AMPK level was high, and phospho-mTOR was low in CSE-treated cells compared to control indicating a nutrient-deprived condition conducive to autophagic induction. The resulting autophagosomes were LC3II positive. However, at the end of this phase, the phospho- AMPK level was reduced, and the phospho-mTOR level became high. The number of autophagosomes got reduced, but they became larger in size, indicating their fusion with lysosomes. All these suggest the reversal of nutrient-depleted situations; thus, this phase is considered beneficial. On the other hand, the second phase ended with apoptosis. Similar to the first phase, the second phase commenced with high phospho-AMPK and low phospho-mTOR. While the autophagosome population increased, most of them failed to fuse with lysosomes due to CSE-mediated microtubule disruption, which subsequently triggered apoptosis. Thus, instead of reverting nutrient deficiency, it caused cellular death, and therefore, the second phase is cytotoxic. Thus, the current study provides insight into how CSE-induced autophagy, while not initially detrimental, may lead to apoptotic cell death.