Skip to main content
SpringerLink
Log in

Mitochondrial Transplantation: A Breakthrough Approach for Cancer Treatment

  • Chapter
  • First Online:
Interdisciplinary Cancer Research

Part of the book series: Interdisciplinary Cancer Research

Abstract

Mitochondria, essential organelles intricately involved in cellular processes, play a crucial role in cancer progression and the development of chemotherapeutic resistance. Mitochondrial transplantation, an innovative procedure to transfer healthy mitochondria to cells with dysfunctional counterparts, holds great potential in treating mitochondria-based diseases, including cancer. Various methods have been proposed for the isolation and transplantation of mitochondria, which differ depending on the type of study. Based on recent findings, four main mechanisms are involved in mitochondrial transplantation, which includes tunneling nanotubes (TNTs), extracellular vesicles, and cellular fusion. Preclinical studies have shown promising outcomes, including improvements in cell cycle regulation, cellular energy metabolism, and modulation of cancer progression. In this chapter, we aim to provide a comprehensive review of the pivotal role of mitochondria in cancer. We endeavor to investigate the impact of mitochondrial transplantation on targeted cells and cancer progression, explore diverse methods and mechanisms of mitochondrial transplantation, and discuss the challenges associated with implementing this approach.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Arnold PK, Finley LWS (2023) Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem 299:102838

    Google Scholar 

  • Bahar E, Han S-Y, Kim J-Y, Yoon H (2022) Chemotherapy resistance: role of mitochondrial and autophagic components. Cancers 14:1462

    Google Scholar 

  • Bittins M, Wang X (2017) TNT-induced phagocytosis: tunneling nanotubes mediate the transfer of pro-phagocytic signals from apoptotic to viable cells. J Cell Physiol 232:2271–2279

    Google Scholar 

  • Bodenstein DF, Powlowski P, Zachos KA, El Soufi El Sabbagh D, Jeong H, Attisano L, Edgar L, Wallace DC, Andreazza AC (2023) Optimization of differential filtration-based mitochondrial isolation for mitochondrial transplant to cerebral organoids. Stem Cell Res Ther 14:202

    Google Scholar 

  • Bukoreshtliev NV, Wang X, Hodneland E, Gurke S, Barroso JF, Gerdes H-H (2009) Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett 583:1481–1488

    Google Scholar 

  • Bury AG, Vincent AE, Turnbull DM, Actis P, Hudson G (2020) Mitochondrial isolation: when size matters. Wellcome Open Res 5

    Google Scholar 

  • Caicedo A, Fritz V, Brondello J-M, Ayala M, Dennemont I, Abdellaoui N, de Fraipont F, Moisan A, Prouteau CA, Boukhaddaoui H (2015) MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 5:9073

    Google Scholar 

  • Celik A, Orfany A, Dearling J, del Nido PJ, McCully JD, Bakar-Ates F (2023) Mitochondrial transplantation: effects on chemotherapy in prostate and ovarian cancer cells in vitro and in vivo. Biomed Pharmacother 161:114524

    Google Scholar 

  • Chang J-C, Liu K-H, Li Y-C, Kou S-J, Wei Y-H, Chuang C-S, Hsieh M, Liu C-S (2013) Functional recovery of human cells harbouring the mitochondrial DNA mutation MERRF A8344G via peptide-mediated mitochondrial delivery. Neurosignals 21:160–173

    Google Scholar 

  • Chang J-C, Chang H-S, Wu Y-C, Cheng W-L, Lin T-T, Chang H-J, Kuo S-J, Chen S-T, Liu C-S (2019) Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer. J Exp Clin Cancer Res 38:30

    Google Scholar 

  • Chen Y, Zhou Z, Min WJ (2018) Mitochondria, oxidative stress and innate immunity. Front Physiol 9:1487

    Google Scholar 

  • Cheng G, Zielonka J, Dranka BP, McAllister D, Mackinnon AC Jr, Joseph J, Kalyanaraman B (2012) Mitochondria-targeted drugs synergize with 2-deoxyglucose to trigger breast cancer cell death. Cancer Res 72:2634–2644

    Google Scholar 

  • Clemente-Suárez VJ, Martín-Rodríguez A, Yáñez-Sepúlveda R, Tornero-Aguilera JF (2023) Mitochondrial transfer as a novel therapeutic approach in disease diagnosis and treatment. Int J Mol Sci 24:8848

    Google Scholar 

  • Cowan DB, Yao R, Akurathi V, Snay ER, Thedsanamoorthy JK, Zurakowski D, Ericsson M, Friehs I, Wu Y, Levitsky SJ (2016) Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 11:e0160889

    Google Scholar 

  • Cruz-Gregorio A, Aranda-Rivera AK, Amador-Martinez I, Maycotte P (2023) Mitochondrial transplantation strategies in multifaceted induction of cancer cell death. Life Sci 332:122098

    Google Scholar 

  • Cui Q, Wen S, Huang P (2017) Targeting cancer cell mitochondria as a therapeutic approach: recent updates. Future Med Chem 9:929–949

    Google Scholar 

  • DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2:e1600200

    Google Scholar 

  • DeBerardinis RJ, Cheng T (2010) Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 29:313–324

    Google Scholar 

  • Desir S, Dickson EL, Vogel RI, Thayanithy V, Wong P, Teoh D, Geller MA, Steer CJ, Subramanian S, Lou EJ (2016) Tunneling nanotube formation is stimulated by hypoxia in ovarian cancer cells. Oncotarget 7:43150

    Google Scholar 

  • Dong L, Neuzil J (2019) Targeting mitochondria as an anticancer strategy. Cancer Commun 39:1–3

    Google Scholar 

  • Doyle LM, Wang MZ (2019) Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 8:727

    Google Scholar 

  • Drab M, Stopar D, Kralj-Iglič V, Iglič A (2019) Inception mechanisms of tunneling nanotubes. Cells 8

    Google Scholar 

  • Elliott R, Jiang X, Head J (2012) Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. Breast Cancer Res Treat 136:347–354

    Google Scholar 

  • Gäbelein CG, Feng Q, Sarajlic E, Zambelli T, Guillaume-Gentil O, Kornmann B, Vorholt JA (2022) Mitochondria transplantation between living cells. PLoS Biol 20:e3001576

    Google Scholar 

  • Genovese I, Carinci M, Modesti L, Aguiari G, Pinton P, Giorgi C (2021) Mitochondria: insights into crucial features to overcome cancer chemoresistance. Int J Mol Sci 22:4770

    Google Scholar 

  • Ghosh P, Vidal C, Dey S, Zhang L (2020) Mitochondria targeting as an effective strategy for cancer therapy. Int J Mol Sci 21:3363

    Google Scholar 

  • Grasso D, Zampieri LX, Capelôa T, Van de Velde JA, Sonveaux P (2020) Mitochondria in cancer Cell stress. Trends Cancer 4:114

    Google Scholar 

  • Guariento A, Piekarski BL, Doulamis IP, Blitzer D, Ferraro AM, Harrild DM, Zurakowski D, Del Nido PJ, McCully JD, Emani SM (2021) Autologous mitochondrial transplantation for cardiogenic shock in pediatric patients following ischemia-reperfusion injury. J Thorac Cardiovasc Surg 162:992–1001

    Google Scholar 

  • Guerra F, Arbini AA, Moro L (2017) Mitochondria and cancer chemoresistance. Biochimica et Biophysica Acta (BBA)-Bioenerg 1858:686–699

    Google Scholar 

  • Hartwig S, Kotzka J, Lehr S (2015) Isolation and quality control of functional mitochondria. Methods Mol Biol 1264:9–23

    Google Scholar 

  • Hubbard WB, Harwood CL, Prajapati P, Springer JE, Saatman KE, Sullivan PG (2019) Fractionated mitochondrial magnetic separation for isolation of synaptic mitochondria from brain tissue. Sci Rep 9:9656

    Google Scholar 

  • Jash E, Prasad P, Kumar N, Sharma T, Goldman A, Sehrawat SJ (2018) Perspective on nanochannels as cellular mediators in different disease conditions. Cell Commun Signal 16:1–9

    Google Scholar 

  • Jenner A, Peña-Blanco A, Salvador-Gallego R, Ugarte-Uribe B, Zollo C, Ganief T, Bierlmeier J, Mund M, Lee JE, Ries J, Schwarzer D, Macek B, Garcia-Saez AJ (2022) DRP1 interacts directly with BAX to induce its activation and apoptosis. EMBO J 41:e108587

    Google Scholar 

  • Kim MJ, Hwang JW, Yun C-K, Lee Y, Choi Y-S (2018) Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep 8:3330

    Google Scholar 

  • Kim JS, Lee S, Kim W-K, Han B-S (2023) Mitochondrial transplantation: an overview of a promising therapeutic approach. BMB Rep 56:488

    Google Scholar 

  • Korenkova O, Pepe A, Zurzolo C (2020) Fine intercellular connections in development: TNTs, cytonemes, or intercellular bridges? Cell Stress 4:30

    Google Scholar 

  • Kretschmer A, Zhang F, Somasekharan SP, Tse C, Leachman L, Gleave A, Li B, Asmaro I, Huang T, Kotula L (2019) Stress-induced tunneling nanotubes support treatment adaptation in prostate cancer. Sci Rep 9:7826

    Google Scholar 

  • Kuznetsov AV, Margreiter R, Ausserlechner MJ, Hagenbuchner J (2022) The complex interplay between mitochondria. ROS and Entire Cellular Metabolism, Antioxidants (Basel), p 11

    Google Scholar 

  • Liao P-C, Bergamini C, Fato R, Pon LA, Pallotti F (2020) Isolation of mitochondria from cells and tissues. Methods Cell Biol 155:3–31

    Google Scholar 

  • Liu Z, Sun Y, Qi Z, Cao L, Ding S (2022) Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases. Cell Biosci 12:1–29

    Google Scholar 

  • Liu X, Zhang Y, Yang X, Zhang Y, Liu Y, Wang L, Yi T, Yuan J, Wen W, Jian YJ, Cell (2023) Mitochondrial transplantation inhibits cholangiocarcinoma cells growth by balancing oxidative stress tolerance through PTEN/PI3K/AKT signaling pathway Tissue Cell 85:102243

    Google Scholar 

  • Lopez J, Tait SW (2015) Mitochondrial apoptosis: killing cancer using the enemy within. Br J Cancer 112:957–962

    Google Scholar 

  • Lou E, O’Hare P, Subramanian S, Steer CJ (2017) Lost in translation: applying 2D intercellular communication via tunneling nanotubes in cell culture to physiologically relevant 3D microenvironments. FEBS J 284:699–707

    Google Scholar 

  • Lou E, Zhai E, Sarkari A, Desir S, Wong P, Iizuka Y, Yang J, Subramanian S, McCarthy J, Bazzaro M, Steer CJ (2018) Cellular and molecular networking within the ecosystem of cancer cell communication via tunneling nanotubes. Front Cell Dev Biol 6:95

    Google Scholar 

  • Luo Y, Ma J, Lu W (2020) The significance of mitochondrial dysfunction in cancer. Int J Mol Sci 21

    Google Scholar 

  • Macheiner T, Fengler VHI, Agreiter M, Eisenberg T, Madeo F, Kolb D, Huppertz B, Ackbar R, Sargsyan K (2016) Magnetomitotransfer: an efficient way for direct mitochondria transfer into cultured human cells. Sci Rep 6:35571

    Google Scholar 

  • Marlein CR, Piddock RE, Mistry JJ, Zaitseva L, Hellmich C, Horton RH, Zhou Z, Auger MJ, Bowles KM, Rushworth SA (2019) CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res 79:2285–2297

    Google Scholar 

  • McGarry JD, Brown NF (1997) The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. Eur J Biochem 244:1–14

    Google Scholar 

  • Nolfi-Donegan D, Braganza A, Shiva S (2020) Mitochondrial electron transport chain: oxidative phosphorylation, oxidant production, and methods of measurement. Redox Biol 37:101674

    Google Scholar 

  • Paliwal S, Chaudhuri R, Agrawal A, Mohanty S (2018) Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci 25:1–12

    Google Scholar 

  • Pasquier J, Galas L, Boulangé-Lecomte C, Rioult D, Bultelle F, Magal P, Webb G, Le Foll F (2012) Different modalities of intercellular membrane exchanges mediate cell-to-cell p-glycoprotein transfers in MCF-7 breast cancer cells. J Biol Chem 287:7374–7387

    Google Scholar 

  • Popov LD (2021) One step forward: extracellular mitochondria transplantation. Cell Tissue Res 384:607–612

    Google Scholar 

  • Porporato PE, Filigheddu N, Pedro JMB-S, Kroemer G, Galluzzi L (2018) Mitochondrial metabolism and cancer. Cell Res 28:265–280

    Google Scholar 

  • Pour PA, Hosseinian S, Kheradvar A (2021) Mitochondrial transplantation in cardiomyocytes: foundation, methods, and outcomes. Am J Physiol Cell Physiol 321(3):C489–C503

    Google Scholar 

  • Qin Y, Jiang X, Yang Q, Zhao J, Zhou Q, Zhou Y (2021) The functions, methods, and mobility of mitochondrial transfer between cells. Front Oncol 11:672781

    Google Scholar 

  • Ramsay EE, Hogg PJ, Dilda PJ (2011) Mitochondrial metabolism inhibitors for cancer therapy. Pharm Res 28:2731–2744

    Google Scholar 

  • Roth KG, Mambetsariev I, Kulkarni P, Salgia R (2020) The mitochondrion as an emerging therapeutic target in cancer. Trends Mol Med 26:119–134

    Google Scholar 

  • Schiliro C, Firestein BL (2021) Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation. Cells 10

    Google Scholar 

  • Senft D, Ronai ZA (2016) Regulators of mitochondrial dynamics in cancer. Curr Opin Cell Biol 39:43–52

    Google Scholar 

  • Sinha K, Das J, Pal PB, Sil PC (2013) Oxidative stress: the mitochondria-dependent and mitochondria-independent pathways of apoptosis. Arch Toxicol 87:1157–1180

    Google Scholar 

  • Sohoni S, Ghosh P, Wang T, Kalainayakan SP, Vidal C, Dey S, Konduri PC, Zhang L (2019) Elevated Heme synthesis and uptake underpin intensified oxidative metabolism and tumorigenic functions in non-small cell lung cancer cells. Cancer Res 79:2511–2525

    Google Scholar 

  • Spinelli JB, Haigis MC (2018) The multifaceted contributions of mitochondria to cellular metabolism. Nat Cell Biol 20:745–754

    Google Scholar 

  • Sullivan LB, Chandel NS (2014) Mitochondrial reactive oxygen species and cancer. Cancer Metab 2:17

    Google Scholar 

  • Tomita K, Kuwahara Y, Igarashi K, Roudkenar MH, Roushandeh AM, Kurimasa A, Sato T (2021) Mitochondrial dysfunction in diseases, longevity, and treatment resistance: tuning mitochondria function as a therapeutic strategy. Genes 12:1348

    Google Scholar 

  • Torralba D, Baixauli F, Sánchez-Madrid F (2016) Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol 4:107

    Google Scholar 

  • Tulsyan S, Aftab M, Sisodiya S, Khan A, Chikara A, Tanwar P, Hussain S (2022) Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet 13

    Google Scholar 

  • Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E (2017) The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun 482:426–431

    Google Scholar 

  • Valenti D, Vacca RA, Moro L, Atlante A (2021) Mitochondria can cross cell boundaries: an overview of the biological relevance, pathophysiological implications and therapeutic perspectives of intercellular mitochondrial transfer. Int J Mol Sci 22:8312

    Google Scholar 

  • van Gisbergen MW, Voets AM, Starmans MH, de Coo IF, Yadak R, Hoffmann RF, Boutros PC, Smeets HJ, Dubois L, Lambin P (2015) How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models. Mutat Res Rev Mutat Res 764:16–30

    Google Scholar 

  • Vaupel P, Schmidberger H, Mayer A (2019) The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. Int J Radiat Biol 95:912–919

    Google Scholar 

  • Vyas S, Zaganjor E, Haigis MC (2016) Mitochondria and cancer. Cell 166:555–566

    Google Scholar 

  • Wang X, Gerdes H-H (2015) Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Diff 22:1181–1191

    Google Scholar 

  • Wang C, Youle RJ (2009) The role of mitochondria in apoptosis. Annu Rev Genet 43:95–118

    Google Scholar 

  • Wang Y-P, Sharda A, Xu S-N, Van Gastel N, Man CH, Choi U, Leong WZ, Li X, Scadden DT (2021) Malic enzyme 2 connects the Krebs cycle intermediate fumarate to mitochondrial biogenesis. Cell Metab 33(1027–1041):e1028

    Google Scholar 

  • Wang Z-H, Chen L, Li W, Chen L, Wang Y-P (2022) Mitochondria transfer and transplantation in human health and diseases. Mitochondrion 65:80–87

    Google Scholar 

  • Wu T-H, Sagullo E, Case D, Zheng X, Li Y, Hong JS, TeSlaa T, Patananan AN, McCaffery JM, Niazi K (2016) Mitochondrial transfer by photothermal nanoblade restores metabolite profile in mammalian cells. Cell Metab 23:921–929

    Google Scholar 

  • Wu S, Zhang A, Li S, Chatterjee S, Qi R, Segura-Ibarra V, Ferrari M, Gupte A, Blanco E, Hamilton DJ (2018) Polymer functionalization of isolated mitochondria for cellular transplantation and metabolic phenotype alteration. Adv Sci 5:1700530

    Google Scholar 

  • Yamada Y, Ito M, Arai M, Hibino M, Tsujioka T, Harashima H (2020) Challenges in promoting mitochondrial transplantation therapy. Int J Mol Sci 21:6365

    Google Scholar 

  • Yang Y, Karakhanova S, Werner J, Bazhin AV (2013) Reactive oxygen species in cancer biology and anticancer therapy. Curr Med Chem 20:3677–3692

    Google Scholar 

  • Yang Y, Karakhanova S, Hartwig W, D'Haese JG, Philippov PP, Werner J, Bazhin AV (2016) Mitochondria and mitochondrial ROS in cancer: novel targets for anticancer therapy. J Cell Physiol 231:2570–2581

    Google Scholar 

  • Yoshida GJ (2015) Metabolic reprogramming: the emerging concept and associated therapeutic strategies. J Exp Clin Cancer Res 34:111

    Google Scholar 

  • Zampieri LX, Silva-Almeida C, Rondeau JD, Sonveaux P (2021) Mitochondrial transfer in cancer: a comprehensive review. Int J Mol Sci 22:3245

    Google Scholar 

  • Zhang T-g, Miao C-y (2023) Mitochondrial transplantation as a promising therapy for mitochondrial diseases. Acta Pharm Sin B 13:1028–1035

    Google Scholar 

  • Zhou W, Zhao Z, Yu Z, Hou Y, Keerthiga R, Fu A (2022) Mitochondrial transplantation therapy inhibits the proliferation of malignant hepatocellular carcinoma and its mechanism. Mitochondrion 65:11–22

    Google Scholar 

  • Zong WX, Rabinowitz JD, White E (2016) Mitochondria and cancer. Mol Cell 61:667–676

    Google Scholar 

Download references

Acknowledgment

We would like to thank Dr. Noosha Samieefar for her valuable comments on our chapter.

Conflict of Interest

None to declare.

Author information

Authors and Affiliations

  1. Network of Interdisciplinarity in Neonates and Infants (NINI), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Melika Mashhadi, Zahra Taheri, Taha Monadi, Niloofar Masoumi, Fatemeh Nosrati, Mohammadreza Heidari & Jalal Pourahmad

  2. Student Research Committee, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Melika Mashhadi & Niloofar Masoumi

  3. Student Research Committee, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University (IAUPS), Tehran, Iran

    Zahra Taheri

  4. Student Research Committee, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran

    Taha Monadi

  5. Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

    Fatemeh Nosrati

  6. Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran

    Mohammadreza Heidari

  7. Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Jalal Pourahmad

Authors
  1. Melika Mashhadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zahra Taheri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taha Monadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Niloofar Masoumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fatemeh Nosrati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mohammadreza Heidari
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jalal Pourahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jalal Pourahmad .

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mashhadi, M. et al. (2024). Mitochondrial Transplantation: A Breakthrough Approach for Cancer Treatment. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2024_353

Download citation

  • DOI: https://doi.org/10.1007/16833_2024_353

  • Published:

  • Publisher Name: Springer, Cham

Publish with us

Policies and ethics

Search

Navigation