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Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels

View ORCID ProfileNeel S. Singhal, View ORCID ProfileMeirong Bai, View ORCID ProfileEvan M. Lee, Shuo Luo, Kayleigh R. Cook, View ORCID ProfileDengke K. Ma
doi: https://doi.org/10.1101/2020.01.31.929018
Neel S. Singhal
1Department of Neurology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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Meirong Bai
2Cardiovascular Research Institute, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
3Department of Physiology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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Evan M. Lee
2Cardiovascular Research Institute, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
3Department of Physiology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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Shuo Luo
2Cardiovascular Research Institute, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
3Department of Physiology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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Kayleigh R. Cook
2Cardiovascular Research Institute, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
3Department of Physiology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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Dengke K. Ma
2Cardiovascular Research Institute, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
3Department of Physiology, University of California-San Francisco, 555 South Mission Bay Blvd., San Francisco, CA, 94158, USA
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  • For correspondence: dengke.ma@ucsf.edu
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Abstract

Many organisms, from anaerobic bacteria to hibernating ground squirrels, have evolved mechanisms to tolerate severe hypoxia or ischemia. In particular, the arctic ground squirrel (AGS) has been shown to be highly resilient to ischemic and reperfusion injuries, demonstrating an ability to withstand metabolic stress under hibernation conditions. Although physiological adaptations are critical to ischemic tolerance in AGS, little is known about cellular mechanisms underlying intrinsic AGS cell tolerance to metabolic stressors. Through cell survival-based cDNA expression screens and comparative genomics, we have discovered that in AGS, a cytoprotective variant of ATP5G1 helps confer improved mitochondrial metabolism and cell resilience to metabolic stress. ATP5G1 encodes a proton-transporting subunit of the mitochondrial ATP synthase complex. Ectopic expression in mouse cells and CRISPR/Cas9 base editing of the endogenous AGS locus revealed causal roles of one AGS-specific amino acid substitution (leucine-32) in mediating the cytoprotective effects of AGS ATP5G1. We provide evidence that AGS ATP5G1 promotes cell resilience to stress by modulating mitochondrial morphological change and metabolic functions. Thus, our results identify a naturally occurring variant of ATP5G1 from a mammalian hibernator that causally contributes to intrinsic cytoprotection against metabolic stresses.

Footnotes

  • https://ucsf.box.com/s/wsetzswzvupx12sf5bjjxui5bnyn1hpu

  • https://ucsf.box.com/s/aelnc7c1hg2b7sen3cceatpm37nugllq

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 31, 2020.
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Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels
Neel S. Singhal, Meirong Bai, Evan M. Lee, Shuo Luo, Kayleigh R. Cook, Dengke K. Ma
bioRxiv 2020.01.31.929018; doi: https://doi.org/10.1101/2020.01.31.929018
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Cytoprotection by a naturally occurring variant of ATP5G1 in Arctic ground squirrels
Neel S. Singhal, Meirong Bai, Evan M. Lee, Shuo Luo, Kayleigh R. Cook, Dengke K. Ma
bioRxiv 2020.01.31.929018; doi: https://doi.org/10.1101/2020.01.31.929018

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