Mitochondrial NAD+ Controls Nuclear ARTD1-Induced ADP-Ribosylation

作者：Ann-Katrin Hopp, Federico Teloni, Lavinia Bisceglie, Corentin Gondrand, Fabio Raith, Kathrin Nowak, Lukas Muskalla, Anna Howald, Patrick G. A. Pedrioli, Kai Johnsson, Matthias Altmeyer, Deena M. Leslie Pedrioli, Michael O. Hottiger · 发表于：Molecular Cell · 年份：2021 · DOI：10.1016/j.molcel.2020.12.034 · 被引用次数：63 · 研究领域：PARP inhibition in cancer therapy、Calcium signaling and nucleotide metabolism、Sirtuins and Resveratrol in Medicine

In addition to its role as an electron transporter, mitochondrial nicotinamide adenine dinucleotide (NAD + ) is an important co-factor for enzymatic reactions, including ADP-ribosylation. Although mitochondria harbor the most intra-cellular NAD + , mitochondrial ADP-ribosylation remains poorly understood. Here we provide evidence for mitochondrial ADP-ribosylation, which was identified using various methodologies including immunofluorescence, western blot, and mass spectrometry. We show that mitochondrial ADP-ribosylation reversibly increases in response to respiratory chain inhibition. Conversely, H 2 O 2 -induced oxidative stress reciprocally induces nuclear and reduces mitochondrial ADP-ribosylation. Elevated mitochondrial ADP-ribosylation, in turn, dampens H 2 O 2 -triggered nuclear ADP-ribosylation and increases MMS-induced ARTD1 chromatin retention. Interestingly, co-treatment of cells with the mitochondrial uncoupler FCCP decreases PARP inhibitor efficacy. Together, our results suggest that mitochondrial ADP-ribosylation is a dynamic cellular process that impacts nuclear ADP-ribosylation and provide evidence for a NAD + -mediated mitochondrial-nuclear crosstalk.