Abstract
Mechanical forces shape cells and tissues during development and adult homeostasis. In addition, they also signal to cells via mechanotransduction pathways to control cell proliferation, differentiation and death. These processes require metabolism of nutrients for both energy generation and biosynthesis of macromolecules. However, how cellular mechanics and metabolism are connected is still poorly understood. Here, we discuss recent evidence indicating how the mechanical cues exerted by the extracellular matrix (ECM), cell–ECM and cell–cell adhesion complexes influence metabolic pathways. Moreover, we explore the energy and metabolic requirements associated with cell mechanics and ECM remodelling, implicating a reciprocal crosstalk between cell mechanics and metabolism.
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Acknowledgements
Work in the S.D. laboratory is supported by an AIRC Foundation Investigator Grant (21392), a Worldwide Cancer Research Grant (21-0156), and a CARIPARO Foundation Eccellenza 2017 grant. P.R. is a recipient of a Veronesi Foundation postdoctoral fellowship. L.V.-J. is recipient of a Federation of European Biochemical Societies postdoctoral fellowship.
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S.D. conceptualized the article. S.D., C.F., P.R. and L.V.-J. wrote the article and edited the manuscript. All authors approved the final content.
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Glossary
- Mechanical forces
-
Cells in tissues are subjected to multiple forces, including applied, frictional, tension and spring (that is, stretch or compression) forces.
- Tension forces
-
The action–reaction forces acting at the cell–extracellular matrix contact sites, and the opposite of compression.
- Stiffness
-
The extent to which an object resists deformation in response to an applied force.
- Cell geometry
-
Intended here as the degree of cell spreading on an adhesive substratum.
- Dystrophin-associated complexes
-
Specialized protein complexes that anchor muscle cells to their extracellular matrix, which is required to transmit force generated in the muscle cytoskeletal contractile units to the extracellular matrix and to stabilize the plasma membrane during repeated cycles of contraction.
- Progeria
-
A rare autosomal dominant genetic disorder characterized by premature ageing symptoms.
- Myocardin-related transcription factors
-
(MRTFs). Transcription factors whose nucleocytoplasmic shuttling is directly regulated by monomeric actin. They act as co-activators for the DNA-binding protein serum response factor (SRF).
- YAP/TAZ
-
Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), whose activity as co-activators for the TEAD family of DNA-binding proteins is regulated by multiple mechanical cues and by the Hippo pathway.
- Phosphofructokinase
-
(PFK). The rate-limiting glycolytic enzyme that phosphorylates fructose 6-phosphate to fructose 1,6-bisphosphate.
- Glycolysis
-
The cytoplasmic energy-yielding pathway that consists in the breakdown of glucose into two molecules of pyruvate and the production of ATP.
- Mitochondrial respiration
-
The energy-yielding pathway in which the electrochemical gradient generated across the inner mitochondrial membrane by the respiratory chain complexes is exploited to generate ATP by ATP synthase.
- Aldolase
-
Glycolytic enzyme that reversibly converts fructose 1,6-bisphosphate to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
- RHO-family GTPases
-
A family of small monomeric GTPases including RHO proteins, RAC proteins and CDC42 that function as molecular switches in response to chemical or mechanical stimuli to regulate actin organization.
- Phosphoinositide 3-kinase
-
(PI3K). Enzymes involved in the activation of signalling pathways associated with proliferation, survival and motility. Elevated PI3K signalling due to gene mutation or activation by upstream inputs is a hallmark of cancer.
- Metabolomics
-
The systematic study of the composition and relative abundance of the small-molecule metabolites (including sugars, amino acids, lipids, nucleotides and the intermediate molecules involved in their synthesis and degradation) in a cell or tissue.
- Diacylglycerol
-
Lipid species with the structure of a glyceride that can act both as intermediates in lipid biosynthetic pathways and as second-messenger signalling molecules.
- SREBP–SCAP complex
-
The complex formed in the endoplasmic reticulum by SREBP1 and SREBP2 and by the SREBP cleavage-activating proteins (SCAP), which regulates the transport of SREBP to the Golgi apparatus, where it is activated, in response to insufficient cholesterol levels.
- Lipidomics
-
Metabolomic analyses specifically focusing on the lipid species composition.
- Lipid droplets
-
Cellular structures for the storage of neutral lipids.
- Spheroids
-
Three-dimensional cellular aggregates that cells form when cultured on non-adhesive plates, or in conditions offering very low levels of extracellular matrix resistance.
- Saturation
-
The predominance of single chemical bonds between the carbon atoms of a molecule, as opposed to the presence of double bonds that are not yet saturated by hydrogen atoms.
- Cardiolipin
-
Lipid species with the structure of a bisphosphatidylglycerol that constitutes about 20% of the total lipids of the inner mitochondrial membrane.
- Viscoelastic properties
-
The ability of a material to exhibit both viscous and elastic characteristics when undergoing deformation.
- Fatty acid oxidation
-
The process of breaking down a fatty acid molecule into acetyl-CoA molecules to feed the mitochondrial tricarboxylic acid cycle and ATP production.
- Cancer-associated fibroblasts
-
A population of cells found in tumours that are negative for epithelial, endothelial and leukocyte markers, with an elongated morphology, lacking the mutations found within cancer cells and likely deriving from the fibroblastic lineage(s).
- Senescence
-
The irreversible arrest of cell proliferation observed in normal non-transformed cells cultured in vitro, associated with telomere shortening and altered cell function, including altered cell morphology and expression of distinct secretory cytokines.
- Hepatocyte metabolic zonation
-
The spatial organization of the various metabolic pathways and functions of hepatocytes within the liver lobules.
- Tricarboxylic acid cycle
-
A series of chemical reactions occurring in mitochondria and used by cells to release energy by the oxidation of acetyl-CoA molecules derived from carbohydrates, fats or proteins. It is coupled to mitochondrial respiration that produces ATP, but also provides precursors for the synthesis of macromolecules.
- Pentose phosphate pathway
-
A metabolic pathway fuelled by glucose and acting in parallel to glycolysis. It generates NADPH (an antioxidant molecule) and five-carbon sugars for the synthesis of nucleotides.
- Autophagosome
-
A double-membrane vesicle incorporating cellular structures fated to lysosomal degradation in the process of autophagy
- Lipid peroxides
-
The toxic products of the oxidation of membrane lipid molecules, which negatively affect the physical and chemical properties of the membrane lipid bilayers and the biological properties of membrane-associated proteins.
- Epithelial–mesenchymal transition
-
The process by which cells lose epithelial identity and the ability to form stable adherens junctions and gain expression of mesenchymal markers, associated with increased migratory ability.
- Hippo pathway
-
An intracellular signalling pathway centred on the activity of two protein kinase families, the kinases MST1/MST2 and LATS1/LATS2, which phosphorylate the YAP and TAZ proteins, controlling their nucleocytoplasmic shuttling, and thereby their activity as nuclear transcriptional co-activators.
- Central carbon metabolism
-
The metabolic pathways, comprising glycolysis, the pentose phosphate pathway and the tricarboxylic acid cycle, that convert sugars into metabolic precursors.
- Leader cells
-
The cells at the forefront of migration during collective cell migration.
- Phosphocreatine
-
A molecule that provides high-energy phosphates to rapidly recycle ATP, acting in parallel to mitochondrial ATP synthesis.
- AMP-activated protein kinase
-
(AMPK). A key energy-sensing protein kinase activated in response to nutrient stress.
- Energy charge
-
An index used to measure the energy status of cells and calculated from the abundance of adenylate phosphates AMP, ADP and ATP.
- Phosphoglycerate mutase
-
A glycolytic enzyme that converts 3-phosphoglycerate to 2-phosphoglycerate.
- Lipid rafts
-
Discrete lipid domains present in the external side of the plasma membrane. These are enriched in cholesterol, glycosphingolipids, and glycosylphosphatidylinositol-anchored proteins.
- Caveolae
-
Small invaginations of the plasma membrane involved in endocytosis.
- Metalloproteinease
-
A proteolytic enzyme whose catalytic domain involves a metal.
- Isocitrate dehydrogenase 1
-
Cytoplasmic enzyme that mediates the reversible decarboxylation of isocitrate to α-ketoglutarate.
- Oncometabolite
-
A metabolite aberrantly accumulated and causing signalling dysregulation in cancer cells.
- Mesangial cells
-
Specialized cells that surround the capillaries of the glomerulus in the kidney.
- mTOR
-
Mechanistic target of rapamycin (mTOR), a core component of protein complexes involved in nutrient sensing. As a protein kinase, it regulates several processes, including cell growth and survival.
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Romani, P., Valcarcel-Jimenez, L., Frezza, C. et al. Crosstalk between mechanotransduction and metabolism. Nat Rev Mol Cell Biol 22, 22–38 (2021). https://doi.org/10.1038/s41580-020-00306-w
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DOI: https://doi.org/10.1038/s41580-020-00306-w
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