2. Academic Validation
  3. Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila

Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila

  • Proc Natl Acad Sci U S A. 2023 Mar 28;120(13):e2213857120. doi: 10.1073/pnas.2213857120.
Shanshan Guo 1,  Shuang Zhang 2,  Yixiao Zhuang 1,  Famin Xie 1,  Ruwen Wang 2,  Xingyu Kong 1,  Qiongyue Zhang 3 4,  Yonghao Feng 3,  Huanqing Gao 1,  Xingxing Kong 1 3 4,  Tiemin Liu 1 4 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200438, China.
  • 2 School of Exercise and Health, Shanghai Frontiers Science Research Base of Exercise and Metabolic Health, Shanghai University of Sport, Shanghai, 200438, China.
  • 3 Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 4 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China.
  • 5 Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
  • 6 School of Life Sciences, Inner Mongolia University, Hohhot, Inner Mongolia 010021, China.
PMID: 36947517 DOI: 10.1073/pnas.2213857120
Abstract

Poly(ADP-ribose) polymerase-1 (PARP1) has been reported to play an important role in longevity. Here, we showed that the knockdown of the PARP1 extended the lifespan of Drosophila, with particular emphasis on the skeletal muscle. The muscle-specific mutant Drosophila exhibited resistance to starvation and oxidative stress, as well as an increased ability to climb, with enhanced mitochondrial biogenesis and activity at an older age. Mechanistically, the inhibition of PARP1 increases the activity of AMP-activated protein kinase alpha (AMPKα) and mitochondrial turnover. PARP1 could interact with AMPKα and then regulate it via poly(ADP ribosyl)ation (PARylation) at residues E155 and E195. Double knockdown of PARP1 and AMPKα, specifically in muscle, could counteract the effects of PARP1 inhibition in Drosophila. Finally, we showed that increasing lifespan via maintaining mitochondrial network homeostasis required intact PTEN induced kinase 1 (PINK1). Taken together, these data indicate that the interplay between PARP1 and AMPKα can manipulate mitochondrial turnover, and be targeted to promote longevity.

Keywords

PARP1; PARylation; longevity; mitochondria.

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