TY - JOUR
T1 - Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
AU - Yu, Bo
AU - Ma, Jing
AU - Li, Jing
AU - Wang, Dazhi
AU - Wang, Zhigao
AU - Wang, Shusheng
N1 - Funding Information:
We thank Dr. Yiping Chen and Dr. Frank Jones for encouragement and for sharing equipment, Dr. Mary Kay Lobo from University of Maryland for providing Drp1S637A plasmids, and Dr. Wang Wang from University of Washington for providing Drp1-K38A plasmids. S.W. was supported by a Startup fund from Tulane University, NIH Grants EY021862 and EY026069.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5−/− cells, respectively. Young but not aging Pgam5−/− mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
AB - Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1. PGAM5 deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in PGAM5−/− cells, respectively. Young but not aging Pgam5−/− mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
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U2 - 10.1038/s41467-020-16312-7
DO - 10.1038/s41467-020-16312-7
M3 - Article
C2 - 32439975
AN - SCOPUS:85085158208
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2549
ER -