Unraveling the Intricate Molecular Mechanism Between Apoptosis and Autophagy During Cellular Stress

Apoptosis, autophagy and autophagy dependent cell death are important cellular processes with complex and intersecting protein networks; as such, they have been the subjects of intense investigation. Here, we highlight the crucial factors governing the crosstalk between autophagy and apoptosis to describe the mechanisms controlling cell survival and death. We identified the autophagy gene Ulk1 to induce apoptosis by inhibiting the mitochondrial MnSOD enzyme and accentuating the level of mitochondrial reactive oxygen species (ROS). Likely, we found pre-autophagy initiator ATG14 to be interacting with Ulk1 to trigger lipophagy mediated endoplasmic reticulum (ER) stress that induced mitochondrial stress to stimulate apoptosis. Further, we established that cellular stress like serum starvation facilitates anti-apoptotic cIAP1 accumulation in regulating mitophagy through ubiquitination. Moreover, cIAP1-induced mitophagy led to dysfunctional mitochondria resulting in abrogation of mitochondrial oxygen consumption rate that followed to decline in ATP level representing another crucial link between autophagy and apoptosis. We further defined nature of autophagy during cellular stress and serum starvation triggered autophagy doesn’t follow a linear trend when exposed to a prolonged time period of starvation, rather there exists two distinct peaks primary smaller one that arrives at lesser time of stress exposure while the secondary is triggered at a later stage. Protracted cellular stress beyond the secondary peak results in cellular death. Knocking down mTOR disrupts the variation pattern whereas apoptosis gene Bax silencing intensifies the phenomena. The observation highlights that when cells are exposed to stress; an initial primary autophagy peak refluxes certain amount of nutrients in the cell which results in decline of stress for an intermittent period but protracted stress results in a secondary autophagy peak, crossing which the cell is committed to undergo cellular death