Adhesion-mediated mechanosignaling forces mitohormesis

• DOI: 10.1016/j.cmet.2021.04.017
• Publication Date: 2021-05-20T15:02:35Z
• Authors: 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
• Keywords: 0301 basic medicine; Aging; Integrins; Mechanotransduction; mechanotabolism; Medical Biochemistry and Metabolomics; Mechanotransduction, Cellular; Mitochondrial Dynamics; Animals, Genetically Modified; Mice; UPRmt; oxidative stress; Cells, Cultured; Cancer; Microscopy; Cultured; Sodium-Hydrogen Exchanger 1; Microscopy, Confocal; Biological Sciences; tension; Middle Aged; Extracellular Matrix; Mitochondria; Ion Exchange; adhesion; Confocal; Female; Signal Transduction; Adult; 1.1 Normal biological development and functioning; Cells; extracellular matrix; Cell Respiration; 610; Genetically Modified; Time-Lapse Imaging; Endocrinology & Metabolism; 03 medical and health sciences; Underpinning research; Cell Adhesion; cancer; Medical biochemistry and metabolomics; Animals; Humans; Caenorhabditis elegans; aging; mechanical stress; Oxidative Stress; HEK293 Cells; Biochemistry and cell biology; Hyperglycemia; Biochemistry and Cell Biology; Generic health relevance; Cellular; Reactive Oxygen Species; metabolism

AbstractMitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed 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 ageing. However, the physical characteristics of the extracellular matrix are also altered in cancer and in aging tissues. We demonstrate that cells sense the physical properties of the extracellular matrix and activate a mitochondrial stress response that adaptively tunes mitochondrial functionviaSLC9A1-dependent ion exchange and HSF1-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.Graphical Abstract