Journal
EXPERIMENTAL AND MOLECULAR MEDICINE
Volume 54, Issue 12, Pages 2135-2147Publisher
SPRINGERNATURE
DOI: 10.1038/s12276-022-00894-x
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Funding
- National Institutes of Health (NIH)
- [ZIAAG000788]
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This study demonstrates the presence of PARP1 and PARylation in mitochondria, and shows that NAD(+) can stimulate PARylation, with NAD(+)-dependent mtPARP1 activity contributing to mtDNA transcriptional regulation.
PARPs play fundamental roles in multiple DNA damage recognition and repair pathways. Persistent nuclear PARP activation causes cellular NAD(+) depletion and exacerbates cellular aging. However, very little is known about mitochondrial PARP (mtPARP) and poly ADP-ribosylation (PARylation). The existence of mtPARP is controversial, and the biological roles of mtPARP-induced mitochondrial PARylation are unclear. Here, we demonstrate the presence of PARP1 and PARylation in purified mitochondria. The addition of the PARP1 substrate NAD(+) to isolated mitochondria induced PARylation, which was suppressed by treatment with the inhibitor olaparib. Mitochondrial PARylation was also evaluated by enzymatic labeling of terminal ADP-ribose (ELTA). To further confirm the presence of mtPARP1, we evaluated mitochondrial nucleoid PARylation by ADP ribose-chromatin affinity purification (ADPr-ChAP) and PARP1 chromatin immunoprecipitation (ChIP). We observed that NAD(+) stimulated PARylation and TFAM occupancy on the mtDNA regulatory region D-loop, inducing mtDNA transcription. These findings suggest that PARP1 is integrally involved in mitochondrial PARylation and that NAD(+)-dependent mtPARP1 activity contributes to mtDNA transcriptional regulation.
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