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. 2020 Apr 16;21(8):2767. doi: 10.3390/ijms21082767

Figure 2.

Figure 2

Interplay of PARP with MAPK-mediated mitochondrial damage in oxidative stress. (a) Effects of oxidative stress in the absence of PARP inhibition. ROS-induced DNA strand breaks induce excess PARP activation leading to NAD+, then ATP depletion. PARP PARylates both itself and ATF4, and replaces PARylated ATM4 at the promoter of MKP-1 coding DNA region. ROS activates JNK and p38 MAPK, which exaggerate ROS-induced mitochondrial dysfunction, and contributes to cell death caused by energy failure. (b) Effects of oxidative stress in the presence of PARP inhibition. The PARP inhibitor blocks excess PARP activation and NAD+ consumption. ATF4 is not PARylated, therefore is able to bind to the promoter of MKP-1 coding DNA region. MKP-1 mRNA is transcribed, MKP-1 protein is translated and inactivates JNK and p38 MAPK. The antioxidant defences compensate for the ROS-induced mitochondrial damages. Pointed arrows denote activation while arrows with flat end represent inhibition. P indicates phosphorylation. Red and yellow spots designate ADP-ribose and nicotinamide, respectively.