Adhesion-mediated mechanosignaling forces mitohormesis

Kevin M Tharp; Ryo Higuchi-Sanabria; Greg A Timblin; Breanna Ford; Carlos Garzon-Coral; Catherine Schneider; Jonathon M Muncie; Connor Stashko; Joseph R Daniele; Andrew S Moore; Phillip A Frankino; Stefan Homentcovschi; Sagar S Manoli; Hao Shao; Alicia L Richards; Kuei-Ho Chen; Johanna Ten Hoeve; Gregory M Ku; Marc Hellerstein; Daniel K Nomura; Karou Saijo; Jason Gestwicki; Alexander R Dunn; Nevan J Krogan; Danielle L Swaney; Andrew Dillin; Valerie M Weaver

doi:10.1016/j.cmet.2021.04.017

Adhesion-mediated mechanosignaling forces mitohormesis

Cell Metab. 2021 Jul 6;33(7):1322-1341.e13. doi: 10.1016/j.cmet.2021.04.017. Epub 2021 May 20.

Authors

Kevin M Tharp¹, Ryo Higuchi-Sanabria², Greg A Timblin³, Breanna Ford⁴, Carlos Garzon-Coral⁵, Catherine Schneider⁶, Jonathon M Muncie¹, Connor Stashko¹, Joseph R Daniele⁷, Andrew S Moore⁸, Phillip A Frankino², Stefan Homentcovschi², Sagar S Manoli⁹, Hao Shao¹⁰, Alicia L Richards¹¹, Kuei-Ho Chen¹¹, Johanna Ten Hoeve¹², Gregory M Ku¹³, Marc Hellerstein⁶, Daniel K Nomura⁴, Karou Saijo³, Jason Gestwicki¹⁰, Alexander R Dunn¹⁴, Nevan J Krogan¹¹, Danielle L Swaney¹¹, Andrew Dillin², Valerie M Weaver¹⁵

Affiliations

¹ Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Molecular & Cellular Biology, Howard Hughes Medical Institute, University of California Berkeley, Berkeley, CA 94597, USA.
³ Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA; Novartis, Berkeley Center for Proteomics and Chemistry Technologies and Department of Chemistry, University of California Berkeley, Berkeley, CA 94720, USA.
⁵ Chemical Engineering Department, Stanford University, Stanford, CA 94305, USA.
⁶ Novartis, Berkeley Center for Proteomics and Chemistry Technologies and Department of Chemistry, University of California Berkeley, Berkeley, CA 94720, USA.
⁷ MD Anderson Cancer Center, South Campus Research, Houston, CA 77054, USA.
⁸ Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
⁹ Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁰ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
¹¹ Quantitative Biosciences Institute (QBI), J. David Gladstone Institutes, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
¹² UCLA Metabolomics Center, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Diabetes Center, Division of Endocrinology and Metabolism, Department of Medicine, UCSF, San Francisco, CA 94143, USA.
¹⁴ Department of Nutritional Sciences and Toxicology, University of California Berkeley, Berkeley, CA 94720, USA.
¹⁵ Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences and Department of Radiation Oncology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, and The Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: valerie.weaver@ucsf.edu.

Abstract

Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programed cell death. The biochemical milieu is known to affect mitochondrial function and contribute to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of aging. However, the physical characteristics of the extracellular matrix are also altered in cancerous and aging tissues. Here, we demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial function via solute carrier family 9 member A1-dependent ion exchange and heat shock factor 1-dependent transcription. Overall, our data indicate that adhesion-mediated mechanosignaling may play an unappreciated role in the altered mitochondrial functions observed in aging and cancer.

Keywords: UPRmt; adhesion; aging; cancer; extracellular matrix; mechanical stress; mechanotabolism; metabolism; oxidative stress; tension.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Adult
Animals
Animals, Genetically Modified
Caenorhabditis elegans
Cell Adhesion / physiology*
Cell Respiration
Cells, Cultured
Extracellular Matrix / metabolism
Female
HEK293 Cells
Humans
Hyperglycemia / metabolism
Hyperglycemia / pathology
Hyperglycemia / physiopathology
Integrins / physiology
Ion Exchange
Mechanotransduction, Cellular / physiology*
Mice
Microscopy, Confocal
Middle Aged
Mitochondria / metabolism
Mitochondria / physiology
Mitochondrial Dynamics / physiology*
Oxidative Stress / physiology
Reactive Oxygen Species / metabolism
Signal Transduction / physiology
Sodium-Hydrogen Exchanger 1 / physiology
Time-Lapse Imaging

Substances

Integrins
Reactive Oxygen Species
Sodium-Hydrogen Exchanger 1

Abstract

Publication types

MeSH terms

Substances

Grants and funding