Recently, it has been recognized that physical abnormalities (e.g. elevated solid stress, elevated interstitial fluid pressure, increased stiffness) are associated with tumor progression and development. Additionally, these mechanical forces originating from tumor cell environment through mechanotransduction pathways can affect metabolism. On the other hand, mitochondria are well-known as bioenergetic, biosynthetic, and signaling organelles crucial for sensing stress and facilitating cellular adaptation to the environment and physical stimuli. Disruptions in mitochondrial dynamics and function have been found to play a role in the initiation and advancement of cancer. Consequently, it is logical to hypothesize that mitochondria dynamics subjected to physical cues may play a pivotal role in mediating tumorigenesis. Recently mitochondrial biogenesis and turnover, fission and fusion dynamics was linked to mechanotransduction in cancer. However, how cancer cell mechanics and mitochondria functions are connected, still remain poorly understood. Here, we discuss recent studies that link mechanical stimuli exerted by the tumor cell environment and mitochondria dynamics and functions. This interplay between mechanics and mitochondria functions may shed light on how mitochondria regulate tumorigenesis.

Department of Optical and Biophysical Systems Institute of Physics of the Czech Academy of Sciences Prague 18200 Czech Republic

Department of Pediatric Research Oslo University Hospital Oslo Norway

Institute for Clinical and Experimental Medicine Prague 14021 Czech Republic

Zobrazit více v PubMed

Saraswathibhatla A, Indana D, Chaudhuri O. Cell-extracellular matrix mechanotransduction in 3D. Nat Rev Mol Cell Biol. 2023;24:495–516. doi: 10.1038/s41580-023-00583-1. PubMed DOI PMC

Uhler C, Shivashankar GV. Regulation of genome organization and gene expression by nuclear mechanotransduction. Nat Rev Mol Cell Biol. 2017;18:717–727. doi: 10.1038/nrm.2017.101. PubMed DOI

Janmey PA, Fletcher DA, Reinhart-King CA. Stiffness sensing by cells. Physiol Rev. 2020;100:695–724. doi: 10.1152/physrev.00013.2019. PubMed DOI PMC

Yamada KM, Doyle AD, Lu JY. Cell-3D matrix interactions: recent advances and opportunities. Trends Cell Biol. 2022;32:883–895. doi: 10.1016/j.tcb.2022.03.002. PubMed DOI PMC

Ladoux B, Mège RM. Mechanobiology of collective cell behaviours. Nat Rev Mol Cell Biol. 2017;18:743–757. doi: 10.1038/nrm.2017.98. PubMed DOI

Romani P, Valcarcel-Jimenez L, Frezza C, Dupont S. Crosstalk between mechanotransduction and metabolism. Nat Rev Mol Cell Biol. 2021;22:22–38. doi: 10.1038/s41580-020-00306-w. PubMed DOI

Du HX, Bartleson JM, Butenko S, Alonso V, Liu WF, Winer DA, et al. Tuning immunity through tissue mechanotransduction. Nat Rev Immunol. 2023;23:174–188. doi: 10.1038/s41577-022-00761-w. PubMed DOI PMC

Di XP, Gao XS, Peng L, Ai JZ, Jin X, Qi SQ, et al. Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets. Signal Transduct Target Ther. 2023;8:282. doi: 10.1038/s41392-023-01501-9. PubMed DOI PMC

Nia HDT, Munn LL, Jain RK. Physical traits of cancer. Science. 2020;370:eaaz0868. doi: 10.1126/science.aaz0868. PubMed DOI PMC

Paul CD, Mistriotis P, Konstantopoulos K. Cancer cell motility: lessons from migration in confined spaces. Nat Rev Cancer. 2017;17:131–140. doi: 10.1038/nrc.2016.123. PubMed DOI PMC

Broders-Bondon F, Ho-Bouldoires THN, Fernandez-Sanchez ME, Farge E. Mechanotransduction in tumor progression: The dark side of the force. J Cell Biol. 2018;217:1571–1587. doi: 10.1083/jcb.201701039. PubMed DOI PMC

Evers TMJ, Holt LJ, Alberti S, Mashaghi A. Reciprocal regulation of cellular mechanics and metabolism. Nat Metab. 2021;3:456–468. doi: 10.1038/s42255-021-00384-w. PubMed DOI PMC

Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science. 2020;368:eaaw5473. doi: 10.1126/science.aaw5473. PubMed DOI PMC

Sciacovelli M, Oncometabolites Frezza C. Unconventional triggers of oncogenic signalling cascades. Free Radic Biol Med. 2016;100:175–181. doi: 10.1016/j.freeradbiomed.2016.04.025. PubMed DOI PMC

Senft D, Ronai ZA. Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol. 2016;39:43–52. doi: 10.1016/j.ceb.2016.02.001. PubMed DOI PMC

Su EML, Villard C, Mitochondria Manneville JB. At the crossroads between mechanobiology and cell metabolism. Biol Cell. 2023;115 doi: 10.1111/boc.202300010. PubMed DOI

Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial membrane dynamics. Nat Rev Mol Cell Biol. 2020;21:204–224. doi: 10.1038/s41580-020-0210-7. PubMed DOI

Chen W, Zhao HK, Li YS. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct Target Ther. 2023;8:333. doi: 10.1038/s41392-023-01547-9. PubMed DOI PMC

Zanotelli MR, Zhang J, Reinhart-King CA. Mechanoresponsive metabolism in cancer cell migration and metastasis. Cell Metab. 2021;33:1307–1321. doi: 10.1016/j.cmet.2021.04.002. PubMed DOI PMC

Liberti MV, Locasale JW. The warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211–218. doi: 10.1016/j.tibs.2015.12.001. PubMed DOI PMC

Shiraishi T, Verdone JE, Huang J, Kahlert UD, Hernandez JR, Torga G, et al. Glycolysis is the primary bioenergetic pathway for cell motility and cytoskeletal remodeling in human prostate and breast cancer cells. Oncotarget. 2015;6:130–143. doi: 10.18632/oncotarget.2766. PubMed DOI PMC

Humphries BA, Buschhaus JM, Chen YC, Haley HR, Qyli T, Chiang B, et al. Plasminogen activator inhibitor 1 (PAI1) promotes actin cytoskeleton reorganization and glycolytic metabolism in triple-negative breast cancer. Mol Cancer Res. 2019;17:1142–1154. doi: 10.1158/1541-7786.Mcr-18-0836. PubMed DOI PMC

DeBerardinis RJ, Chandel NS. We need to talk about the Warburg effect. Nat Metab. 2020;2:127–129. doi: 10.1038/s42255-020-0172-2. PubMed DOI

Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21:217–238. doi: 10.1038/s41568-020-00329-7. PubMed DOI

Wu MJ, Ren AJ, Xu D, Peng XJ, Ye XH, Li A. Diagnostic performance of elastography in malignant soft tissue tumors: A systematic review and meta-analysis. Ultrasound Med Biol. 2021;47:855–868. doi: 10.1016/j.ultrasmedbio.2020.12.017. PubMed DOI

Boyd NF, Li Q, Melnichouk O, Huszti E, Martin LJ, Gunasekara A, et al. Evidence that breast tissue stiffness is associated with risk of breast cancer. PLoS One. 2014;9 doi: 10.1371/journal.pone.0100937. PubMed DOI PMC

Chen W, Fang LX, Chen HL, Zheng JH. Accuracy of ultrasound elastography for predicting breast cancer response to neoadjuvant chemotherapy: A systematic review and meta-analysis. World J Clin Cases. 2022;10:3436–3448. doi: 10.12998/wjcc.v10.i11.3436. PubMed DOI PMC

Maskarinec G, Pagano IS, Little MA, Conroy SM, Park SY, Kolonel LN. Mammographic density as a predictor of breast cancer survival: the Multiethnic Cohort. Breast Cancer Res. 2013;15:R7. doi: 10.1186/bcr3378. PubMed DOI PMC

Evans A, Whelehan P, Thomson K, Brauer K, Jordan L, Purdie C, et al. Differentiating benign from malignant solid breast masses: value of shear wave elastography according to lesion stiffness combined with greyscale ultrasound according to BI-RADS classification. Br J Cancer. 2012;107:224–229. doi: 10.1038/bjc.2012.253. PubMed DOI PMC

Carrara S, Di Leo M, Grizzi F, Correale L, Rahal D, Anderloni A, et al. EUS elastography (strain ratio) and fractal-based quantitative analysis for the diagnosis of solid pancreatic lesions. Gastrointest Endosc. 2018;87:1464–1473. doi: 10.1016/j.gie.2017.12.031. PubMed DOI

Shahryari M, Tzschätzsch H, Guo J, Garcia SRM, Böning G, Fehrenbach U, et al. Tomoelastography distinguishes noninvasively between benign and malignant liver lesions. Cancer Res. 2019;79:5704–5710. doi: 10.1158/0008-5472.Can-19-2150. PubMed DOI

Rouvière O, Melodelima C, Dinh AH, Bratan F, Pagnoux G, Sanzalone T, et al. Stiffness of benign and malignant prostate tissue measured by shear-wave elastography: a preliminary study. Eur Radiol. 2017;27:1858–1866. doi: 10.1007/s00330-016-4534-9. PubMed DOI

Merino MM, Levayer R, Moreno E. Survival of the fittest: essential roles of cell competition in development, aging, and cancer. Trends Cell Biol. 2016;26:776–788. doi: 10.1016/j.tcb.2016.05.009. PubMed DOI

Papalazarou V, Zhang T, Paul NR, Juin A, Cantini M, Maddocks ODK, et al. The creatine-phosphagen system is mechanoresponsive in pancreatic adenocarcinoma and fuels invasion and metastasis. Nat Metab. 2020;2:62–80. doi: 10.1038/s42255-019-0159-z. PubMed DOI PMC

Guo L, Cui CH, Zhang K, Wang JX, Wang YL, Lu YX, et al. Kindlin-2 links mechano-environment to proline synthesis and tumor growth. Nat Commun. 2019;10:845. doi: 10.1038/s41467-019-08772-3. PubMed DOI PMC

Elia I, Rossi M, Stegen S, Broekaert D, Doglioni G, van Gorsel M, et al. Breast cancer cells rely on environmental pyruvate to shape the metastatic niche. Nature. 2019;568:117–121. doi: 10.1038/s41586-019-0977-x. PubMed DOI PMC

Mookerjee SA, Goncalves RLS, Gerencser AA, Nicholls DG, Brand MD. The contributions of respiration and glycolysis to extracellular acid production. Biochim Biophys Acta-Bioenerg. 2015;1847:171–181. doi: 10.1016/j.bbabio.2014.10.005. PubMed DOI

Wellen KE, Thompson CB. A two-way street: reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol. 2012;13:270–276. doi: 10.1038/nrm3305. PubMed DOI

Weinberg SE, Sena LA, Chandel NS. Mitochondria in the regulation of innate and adaptive immunity. Immunity. 2015;42:406–417. doi: 10.1016/j.immuni.2015.02.002. PubMed DOI PMC

Lightowlers RN, Taylor RW, Turnbull DM. Mutations causing mitochondrial disease: What is new and what challenges remain? Science. 2015;349:1494–1499. doi: 10.1126/science.aac7516. PubMed DOI

Mishra P, Carelli V, Manfredi G, Chan DC. Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation. Cell Metab. 2014;19:630–641. doi: 10.1016/j.cmet.2014.03.011. PubMed DOI PMC

Jiao HF, Jiang D, Hu XY, Du WQ, Ji LL, Yang YZ, et al. Mitocytosis, a migrasome-mediated mitochondrial quality-control process. Cell. 2021;184 doi: 10.1016/j.cell.2021.04.027. 2896-910.e13. PubMed DOI

Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–1065. doi: 10.1126/science.1219855. PubMed DOI PMC

Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–360. doi: 10.1042/Ebc20170104. PubMed DOI PMC

Wallace DC. Mitochondria and cancer. Nat Rev Cancer. 2012;12:685–698. doi: 10.1038/nrc3365. PubMed DOI PMC

Breda CND, Davanzo GG, Basso PJ, Camara NOS, Moraes-Vieira PMM. Mitochondria as central hub of the immune system. Redox Biol. 2019;26 doi: 10.1016/j.redox.2019.101255. PubMed DOI PMC

Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46. doi: 10.1158/2159-8290.Cd-21-1059. PubMed DOI

Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ. BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene. 2013;32:4748–4757. doi: 10.1038/onc.2012.500. PubMed DOI

Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell. 2015;57:537–551. doi: 10.1016/j.molcel.2015.01.002. PubMed DOI PMC

Tian GA, Xu WT, Zhang XL, Zhou YQ, Sun Y, Hu LP, et al. CCBE1 promotes mitochondrial fusion by inhibiting the TGF3-DRP1 axis to prevent the progression of hepatocellular carcinoma. Matrix Biol. 2023;117:31–45. doi: 10.1016/j.matbio.2023.02.007. PubMed DOI

Liu XW, Sun J, Yuan P, Shou KQ, Zhou YH, Gao WQ, et al. Mfn2 inhibits proliferation and cell-cycle in Hela cells via Ras-NF-κB signal pathway. Cancer Cell Int. 2019;19:197. doi: 10.1186/s12935-019-0916-9. PubMed DOI PMC

Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene. 2013;32:4814–4824. doi: 10.1038/onc.2012.494. PubMed DOI PMC

Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature. 2019;575:299–309. doi: 10.1038/s41586-019-1730-1. PubMed DOI PMC

Fu YQ, Dong W, Xu YT, Li L, Yu X, Pang YH, et al. Targeting mitochondrial dynamics by AZD5363 in triple-negative breast cancer MDA-MB-231 cell-derived spheres. Naunyn-Schmiedebergs Arch Pharmacol. 2023;396:2545–2553. doi: 10.1007/s00210-023-02477-7. PubMed DOI PMC

Romani P, Nirchio N, Arboit M, Barbieri V, Tosi A, Michielin F, et al. Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nat Cell Biol. 2022;24:168–180. doi: 10.1038/s41556-022-00843-w. PubMed DOI PMC

Archer SL. Mitochondrial dynamics - mitochondrial fission and fusion in human diseases. N Engl J Med. 2013;369:2236–2251. doi: 10.1056/NEJMra1215233. PubMed DOI

Min E, Schwartz MA. Translocating transcription factors in fluid shear stress-mediated vascular remodeling and disease. Exp Cell Res. 2019;376:92–97. doi: 10.1016/j.yexcr.2019.01.005. PubMed DOI PMC

Petridou NI, Spiró Z, Heisenberg CP. Multiscale force sensing in development. Nat Cell Biol. 2017;19:581–588. doi: 10.1038/ncb3524. PubMed DOI

Tschumperlin DJ, Ligresti G, Hilscher MB, Shah VH. Mechanosensing and fibrosis. J Clin Invest. 2018;128:74–84. doi: 10.1172/Jci93561. PubMed DOI PMC

Vining KH, Mooney DJ. Mechanical forces direct stem cell behaviour in development and regeneration. Nat Rev Mol Cell Biol. 2017;18:728–742. doi: 10.1038/nrm.2017.108. PubMed DOI PMC

Mohammadi H, Sahai E. Mechanisms and impact of altered tumour mechanics. Nat Cell Biol. 2018;20:766–774. doi: 10.1038/s41556-018-0131-2. PubMed DOI

Chen K, Wang Y, Deng X, Guo L, Wu C. Extracellular matrix stiffness regulates mitochondrial dynamics through PINCH-1- and kindlin-2-mediated signalling. Curr Res Cell Biol. 2021;2 doi: 10.1016/j.crcbio.2021.100008. DOI

Tharp KM, Higuchi-Sanabria R, Timblin GA, Ford B, Garzon-Coral C, Schneider C, et al. Adhesion-mediated mechanosignaling forces mitohormesis. Cell Metab. 2021;33 doi: 10.1016/j.cmet.2021.04.017. 1322-41.e13. PubMed DOI PMC

Xie J, Bao M, Hu XY, Koopman WJH, Huck WTS. Energy expenditure during cell spreading influences the cellular response to matrix stiffness. Biomaterials. 2021;267 doi: 10.1016/j.biomaterials.2020.120494. PubMed DOI

Guo T, Jiang CS, Yang SZ, Zhu Y, He C, Carter AB, et al. Mitochondrial fission and bioenergetics mediate human lung fibroblast durotaxis. JCI Insight. 2023;8 doi: 10.1172/jci.insight.157348. PubMed DOI PMC

Yanes B, Rainero E. The interplay between cell-extracellular matrix interaction and mitochondria dynamics in cancer. Cancers. 2022;14:1433. doi: 10.3390/cancers14061433. PubMed DOI PMC

Zanotelli MR, Goldblatt ZE, Miller JP, Bordeleau F, Li J, VanderBurgh JA, et al. Regulation of ATP utilization during metastatic cell migration by collagen architecture. Mol Biol Cell. 2018;29:1–9. doi: 10.1091/mbc.E17-01-0041. PubMed DOI PMC

Frtus A, Smolkov B, Uzhytchak M, Lunova M, Jirsa M, Petrenko Y, et al. Mechanical regulation of mitochondrial dynamics and function in a 3D-engineered liver tumor microenvironment. ACS Biomater Sci Eng. 2023;9:2408–2425. doi: 10.1021/acsbiomaterials.2c01518. PubMed DOI PMC

Helle SCJ, Feng Q, Aebersold MJ, Hirt L, Grüter RR, Vahid A, et al. Mechanical force induces mitochondrial fission. Elife. 2017;6:e30292. doi: 10.7554/eLife.30292. PubMed DOI PMC

Pang GF, Xie Q, Yao JJ. Mitofusin 2 inhibits bladder cancer cell proliferation and invasion via the Wnt/β-catenin pathway. Oncol Lett. 2019;18:2434–2442. doi: 10.3892/ol.2019.10570. PubMed DOI PMC

Xu K, Chen G, Li XB, Wu XQ, Chang ZJ, Xu JH, et al. MFN2 suppresses cancer progression through inhibition of mTORC2/Akt signaling. Sci Rep. 2017;7:41718. doi: 10.1038/srep41718. PubMed DOI PMC

Chen L, Zhang J, Lyu ZM, Chen YB, Ji XY, Cao HY, et al. Positive feedback loop between mitochondrial fission and Notch signaling promotes survivin-mediated survival of TNBC cells. Cell Death Dis. 2018;9:1050. doi: 10.1038/s41419-018-1083-y. PubMed DOI PMC

Lin ZCA, Lin XY, Chen JH, Huang GQ, Chen TG, Zheng LL. Mitofusin-2 is a novel anti-angiogenic factor in pancreatic cancer. J Gastrointest Oncol. 2021;12:484–495. doi: 10.21037/jgo-21-176. PubMed DOI PMC

You M-H, Jeon MJ, Sr Kim, Lee WK, Cheng S-y, Jang G, et al. Mitofusin-2 modulates the epithelial to mesenchymal transition in thyroid cancer progression. Sci Rep. 2021;11:2054. doi: 10.1038/s41598-021-81469-0. PubMed DOI PMC

Kitamura S, Yanagi T, Imafuku K, Hata H, Abe R, Shimizu H. Drp1 regulates mitochondrial morphology and cell proliferation in cutaneous squamous cell carcinoma. J Dermatol Sci. 2017;88:298–307. doi: 10.1016/j.jdermsci.2017.08.004. PubMed DOI

Xie Q, Wu QL, Horbinski CM, Flavahan WA, Yang KL, Zhou WC, et al. Mitochondrial control by DRP1 in brain tumor initiating cells. Nat Neurosci. 2015;18:501–510. doi: 10.1038/nn.3960. PubMed DOI PMC

Yin MJ, Lu Q, Liu X, Wang T, Liu Y, Chen LF. Silencing Drp1 inhibits glioma cells proliferation and invasion by RHOA/ROCK1 pathway. Biochem Biophys Res Commun. 2016;478:663–668. doi: 10.1016/j.bbrc.2016.08.003. PubMed DOI

Huang QC, Zhan L, Cao HY, Li JB, Lyu YH, Guo X, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12:999–1014. doi: 10.1080/15548627.2016.1166318. PubMed DOI PMC