AMPK mediates a pro-survival autophagy downstream of PARP-1 activation in response to DNA alkylating agents

In this study we aim to elucidate the signaling pathway and biological function of autophagy induced by MNNG, a commonly used DNA alkylating agent. We first observed that MNNG is able to induce necrotic cell death and autophagy in Bax−/− Bak−/− double knockout MEFs. We analyzed the critical role of PARP-1 activation and ATP depletion in MNNG-mediated cell death and autophagy via AMPK activation and mTOR suppression. We provide evidence that suppression of AMPK blocks MNNG-induced autophagy and enhances cell death, suggesting the pro-survival function of autophagy in MNNG-treated cells. Taken together, data from this study reveal a novel mechanism in controlling MNNG-mediated autophagy via AMPK activation downstream of PARP-1 activation and ATP depletion.

► MNNG induces necrotic cell death and autophagy in Bax−/− Bak−/− DKO MEFs, via PARP-1 activation and ATP depletion. ► PARP-1 activation and ATP depletion lead to AMPK activation, mTOR suppression and induction of autophagy. ► Autophagy plays a pro-survival function in MNNG-mediated necrotic cell death.