Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate

Abstract

Mitochondria are highly dynamic organelles and respond to stress by changing their fission-fusion cycle, undergoing mitophagy, or releasing apoptotic proteins to initiate cell death. The molecular mechanisms that sense different stresses and coordinate distinct effectors still await full characterization. Here, we show that PGAM5, which exists in an equilibrium between dimeric and multimeric states, dephosphorylates BCL-xL to inhibit apoptosis or FUNDC1 to activate mitofission and mitophagy in response to distinct stresses. In vinblastine-treated cells, PGAM5 dephosphorylates BCL-xL at Ser62 to restore BCL-xL sequestration of BAX and BAK and thereby resistance to apoptosis. Selenite-induced oxidative stress increases the multimerization of PGAM5, resulting in its dissociation from BCL-xL, which causes increased BCL-xL phosphorylation and apoptosis. Once freed, the more multimeric and active PGAM5 dephosphorylates FUNDC1 to initiate mitofission and mitophagy. The reciprocal interaction of PGAM5 with FUNDC1 and BCL-xL, controlled by PGAM5 multimerization, serves as a molecular switch between mitofission/mitophagy and apoptosis.

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Acknowledgements

This research was supported by Grants 301520103904, 91754114, 31271529, 31671441 and 3192100015 from the Natural Science Foundation of China to YZ and QC, Grants 2016YFA0500201 and 2016YFA0100503 from the Ministry of Science and Technology of China to QC, Grant QYZDJ-SSW-SMC004 from the CAS Key Project of Frontier Science, 111 Project from the Ministry of Education and the State Administration of Foreign Experts Affairs of the People’s Republic of China (B08011), Grant R01GM062964 from the United States National Institutes of Health and Grant HR16-026 from the Oklahoma Center for the Advancement of Science and Technology to JL, and by an Institutional Development Award from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103640.

Author information

KM conceived and designed the experiments with YZ, JL and QC; KM performed most of the experiments and data analysis with assistance from RC, HC, MC, TZ, BC, CM and QL. ZZ performed the photocrosslinking experiment. KM, QC, JL and YZ wrote the manuscript. All authors provided intellectual input to the manuscript.

Correspondence to Jialing Lin or Yushan Zhu or Quan Chen.

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Ma, K., Zhang, Z., Chang, R. et al. Dynamic PGAM5 multimers dephosphorylate BCL-xL or FUNDC1 to regulate mitochondrial and cellular fate. Cell Death Differ 27, 1036–1051 (2020). https://doi.org/10.1038/s41418-019-0396-4

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