Curcumin, a Multifaceted Hormetic Agent, Mediates an Intricate Crosstalk between Mitochondrial Turnover, Autophagy, and Apoptosis

Figure 10

Crosstalk between apoptosis and autophagy in cells treated with curcumin. Curcumin mainly targets the endoplasmic reticulum (ER) and lysosomes. The classic apoptotic pathway is mediated by calcium release from the ER. Uptake of this calcium by mitochondria disrupts mitochondrial homeostasis. Calcium alters mitochondrial electron transport causing substantial ROS production (both superoxide anions and hydrogen peroxide), which leads to the opening of the permeability transition pore in the mitochondrial membrane. Consequently, cytochrome c is released and the caspase-9 and caspase-3/7 pathway is activated leading to cell death. Furthermore, the ER stress pathway leads to the formation of autophagic vacuoles that attempt to eliminate the dysfunctional mitochondria. The cleavage of beclin-1 is associated with early apoptosis and leads to the accumulation of autophagic vacuoles. So, despite the activation of autophagy, cells undergo a type of “necrotic cell death” following these initial apoptotic events. These two pathways are in parallel to a lysosomal pathway that is dependent on curcumin concentration (see Figure 4). Curcumin destabilizes lysosomal membranes leading to lysosomal membrane permeability and the activation of both cathepsins and chemotrypsins. Activated caspase-8 leads to beclin-1 cleavage that inhibits the primarily induced autophagy. The increase in cytosolic calcium concentration also activates calpains, which contribute to the degradation process and accelerate cell death. The various inhibitors used in this work are indicated in red at the place where the pathways are affected ([2, 39]; and Patrice X. Petit personnal communication). Big gray arrows indicate the entrance of the three main pathways that interfere (primary cell death pathway, secondary lysosomal cell death pathway, and autophagic pathway).