Ulyanovsk Medico-biological Journal

REVIEWS

Download article

DOI 10.34014/2227-1848-2023-3-14-29

MECHANISMS OF NATURAL MITOCHONDRIAL TRANSFER IN HEALTH AND IN CANCER

O.I. Kit, E.M. Frantsiyants, A.I. Shikhlyarova, I.V. Neskubina

National Medical Research Center for Oncology, Ministry of Health of the Russian Federation,
Rostov-on-Don, Russia

 

This review discusses issues related to mitochondrial dynamics. It also highlights mechanisms allowing these organelles to transcend cell boundaries and transfer between mammalian cells. Mitochondria play a key role in energy generation and cellular physiological processes. These organelles are highly dynamic; they constantly change their morphology, cellular location, and distribution in response to cellular stress.

In recent years, the phenomenon of mitochondrial transfer has attracted significant attention and interest from biologists and medical investigators. Intercellular mitochondrial transfer occurs in a different way, including tunneling nanotubes (TNTs), extracellular vesicles (EVS), and gap junction channels (GJCs). According to research on intercellular mitochondrial transfer in physiological and pathological environments, mitochondrial transfer has great potential for maintaining body homeostasis and regulating pathological processes. Recent evidence also suggests, that cell-free mitochondria release into blood under normal and pathological conditions (stress, trauma). They were found as circulating extracellular mitochondria in blood samples from mica and humans. Multiple research groups have developed artificial mitochondrial transfer/transplantation (AMT/T) methods that transfer healthy mitochondria into damaged cells and recover cellular function. This paper reviews intercellular spontaneous mitochondrial transfer modes, mechanisms, and the latest methods of AMT/T. Furthermore, potential application value and mechanism of AMT/T in disease treatment (including malignant neoplasms) are also discussed.

Key words: mitochondria, malignant neoplasms, natural mitochondrial transfer, pathological mitochondrial transfer.

 

Conflict of interest. The authors declare no conflict of interest.

Author contributions

Text writing, data analysis and interpretation: Frantsiyants E.M.

Scientific editing: Kit O.I., Shikhlyarova A.I.

Technical editing, reference design: Neskubina I.V.

 

References

  1. Frantsiyants E.M., Neskubina I.V., Cheryarina N.D., Surikova E.I., Shikhlyarova A.I., Bandovkina V.A., Nemashkalova L.A., Kaplieva I.V., Trepitaki L.K., Kachesova P.S., Kotieva I.M., Morozova M.I., Pogorelova Yu.A. Funktsional'noe sostoyanie mitokhondriy kardiomiotsitov pri zlokachestvennom protsesse na fone komorbidnoy patologii v eksperimente [Functional state of cardiomyocyte mitochondria in malignant process in comorbid pathology in experiment]. Yuzhno-Rossiyskiy onkologicheskiy zhurnal. 2021; 2 (3): 13–22 (in Russian).

  2. Kit O.I., Frantsiyants E.M., Neskubina I.V., Surikova E.I., Kaplieva I.V., Bandovkina V.A. Vliyanie varianta razvitiya melanomy V16/F10 na soderzhanie kal'tsiya v mitokhondriyakh razlichnykh organov samok myshey [Influence of B16/F10 melanoma growth variant on calcium levels in mitochondria in various organs of female mice]. Issledovaniya i praktika v meditsine. 2021; 8 (1): 20–29 (in Russian).

  3. Heineman B.D., Liu X., Wu G.Y. Targeted Mitochondrial Delivery to Hepatocytes: A Review. Journal of clinical and translational hepatology. 2022; 10 (2): 321–328.

  4. Porat-Shliom N., Harding O.J., Malec L., Narayan K., Weigert R. Mitochondrial Populations Exhibit Differential Dynamic Responses to Increased Energy Demand during Exocytosis In Vivo. Science. 2019; 11: 440–449.

  5. Roy S., Kim D., Sankaramoorthy A. Mitochondrial structural changes in the pathogenesis of diabetic retinopathy. J. Clin. Med. 2019; 8 (9): 1363.

  6. Su B.K., Lee S.A., Pak K., Su Wu, Kim S.J., Woo Wu. Disbindin, associated with schizophrenia, modulates mitochondrial axonal movement in collaboration with p150 glued. Molbrain. 2021; 14 (1): 14.

  7. Valenti D., Vacca R.A., Moro L., Atlante A. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer. International journal of molecular sciences. 2021; 22 (15): 8312.

  8. Singh B., Modica-Napolitano J.S., Singh K.K. Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin. Cancer Biol. 2017; 47: 1–17.

  9. Shanmughapriya S., Langford D., Natarajaseenivasan K. Inter and Intracellular mitochondrial trafficking in health and disease. Ageing Res. Rev. 2020; 62: 101128.

  10. Liu Z., Sun Y., Qi Z., Cao L., Ding S. Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases. Cell & bioscience. 2022; 12 (1): 66.

  11. Liu D., Gao Y., Liu J., Huang Y., Yin J., Feng Y. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct. Target. Ther. 2021; 6: 1–18.

  12. Zampieri L.X., Silva-Almeida C., Rondeau J.D., Sonveaux P. Mitochondrial Transfer in Cancer: A Comprehensive Review. Int J Mol Sci. 2021; 22 (6): 3245.

  13. Torralba D., Baixauli F., Sánchez-Madrid F. Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016; 4: 107.

  14. Paliwal S., Chaudhuri R., Agrawal A., Mohanty S. Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci. 2018; 25 (1): 31.

  15. Li H., Wang C., He T., Zhao T., Chen Y.Y., Shen Y.L. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics. 2019; 9 (7): 2017–2035.

  16. Gollihue J.L., Patel S.P., Mashburn C., Eldahan K.C., Sullivan P.G., Rabchevsky A.G. Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures. J. Neurosci. Methods. 2017; 287: 1–12.

  17. Chang J.C., Hoel F., Liu K.H., Wei Y.H., Cheng F.C., Kuo S.J. Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation. Sci Rep. 2017; 7 (1): 10710.

  18. Liu X., Khouri-Farah N., Wu C.H., Wu G.Y. Targeted delivery of mitochondria to the liver in rats. J. Gastroenterol. Hepatol. 2020; 35 (12): 2241–2247.

  19. Dong L.-F., Kovarova J., Bajzikova M., Bezawork-Geleta A., Svec D., Endaya B. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife. 2017; 6: e22187.

  20. Delvaeye T., Vandenabeele P., Bultynck G., Leybaert L., Krysko D.V. Therapeutic Targeting of Connexin Channels: New Views and Challenges. Trends Mol Med. 2018; 24 (12): 1036–1053.

  21. Morrison T.J., Jackson M.V., Cunningham E.K., Kissenpfennig A., McAuley D., O’Kane C. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017; 196: 1275–1286. DOI: https://doi.org/10.1164/rccm.201701-0170OC.

  22. Qin Y., Jiang X., Yang Q., Zhao J., Zhou Q., Zhou Y. The Functions, Methods, and Mobility of Mitochondrial Transfer Between Cells. Front. Oncol. 2021; 11: 672781.

  23. Austefjord M.W., Gerdes H.H., Wang X. Tunneling nanotubes: diversity in morphology and structure. Commun Integr Biol. 2014; 7 (1): e27934.

  24. Vignais M.L., Caicedo A., Brondello J.M. Cell connections by tunneling nanotubes: effects of mitochondrial trafficking on target cell metabolism, homeostasis, and response to therapy. Stem Cells Int. 2017; 2017: 6917941.

  25. Ljubojevic N., Henderson J.M., Zurzolo C. The ways of actin: why tunneling nanotubes are unique cell protrusions. Trends Cell Biol. 2021; 31 (2): 130–142.

  26. Yang F., Zhang Y., Liu S., Xiao J., He Y., Shao Z. Nanotube-mediated mitochondrial tunneling rescues nucleus pulposus cells from mitochondrial dysfunction and apoptosis. Oxidative cellular longevity. 2022; 2022: 3613319.

  27. Yang C., Endoh M., Tan D.Q., Nakamura-Ishizu A., Takihara Y., Matsumura T., Suda T. Mitochondria transfer from early stages of erythroblasts to their macrophage niche via tunnelling nanotubes. Br. J. Haematol. 2021; 193 (6): 1260–1274.

  28. Wang X., Gerdes H.H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 2015; 22 (7): 1181–1191.

  29. Abraham A., Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Transl. Med. 2020; 9 (1): 28–38.

  30. Meng W., He C., Hao Y., Wang L., Li L., Zhu G. Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source. Drug Deliv. 2020; 27 (1): 585–598.

  31. Varcianna A., Myszczynska M.A., Castelli L.M., O'Neill B., Kim Y., Talbot J. Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS. EBioMedicine. 2019; 40: 626–635.

  32. Hayakawa K., Esposito E., Wang X., Terasaki Y., Liu Y., Xing C. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535 (7613): 551–555.

  33. Nicolás-Ávila J.A., Lechuga-Vieco A.V., Esteban-Martínez L., Sánchez-Díaz M., Díaz-García E., Santiago D.J. A network of macrophages supports mitochondrial homeostasis in the heart. Cell. 2020; 183 (1): 94–109.

  34. Hough K.P., Trevor J.L., Strenkowski J.G., Wang Y., Chacko B.K., Tousif S. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018; 18: 54–64.

  35. Simeone P., Bologna G., Lanuti P., Pierdomenico L., Guagnano M.T., Pieragostino D. Extracellular vesicles as signaling mediators and disease biomarkers across biological barriers. Int. J. Mol. Sci. 2020; 21: 2514.

  36. Sansone P., Savini C., Kurelac I., Chang Q., Amato L.B., Strillacci A. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. USA. 2017; 114: E9066–E9075.

  37. Murray L.M.A., Krasnodembskaya A.D. Concise review: intercellular communication via organelle transfer in the biology and therapeutic applications of stem cells. Stem Cells. 2019; 37 (1): 14–25.

  38. Mohammadalipour A., Dumbali S.P., Wenzel P.L. Mitochondrial transfer and regulators of mesenchymal stromal cell function and therapeutic efficacy. Front Cell Dev Biol. 2020; 8: 603292.

  39. Senos Demarco R., Jones D.L. Mitochondrial fission regulates germ cell differentiation by suppressing ROS-mediated activation of epidermal growth factor signaling in the Drosophila larval testis. Sci. Rep. 2019; 9 (1): 19695.

  40. Alarcon-Martinez L., Villafranca-Baughman D., Quintero H., Kacerovsky J.B., Dotigny F., Murai K.K. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature. 2020; 585 (7823): 91–95.

  41. Pinto G., Saenz-de-Santa-Maria I., Chastagner P., Perthame E., Delmas C., Toulas C. Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids. Biochem J. 2021; 478 (1): 21–39.

  42. Maeda A., Fadeel B. Mitochondria released by cells undergoing TNF-alpha-induced necroptosis act as danger signals. Cell Death Dis. 2014; 5: e1312.

  43. Phinney D.G., Di Giuseppe M., Njah J., Sala E., Shiva S., St Croix C.M. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6: 8472.

  44. Mahrouf-Yorgov M., Augeul L., Da Silva C.C., Jourdan M., Rigolet M., Manin S. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 2017; 24 (7): 1224–1238.

  45. Sahinbegovic H., Jelinek T., Hrdinka M., Bago J.R., Turi M., Sevcikova T. Intercellular Mitochondrial Transfer in the Tumor Microenvironment. Cancers. 2020; 12: 1787.

  46. Nakahira K., Hisata S., Choi A.M. The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases. Antioxid. Redox Signal. 2015; 23: 1329–1350.

  47. Roh J.S., Sohn D.H. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Netw. 2018; 18: e27.

  48. Lu J., Zheng X., Li F., Yu Y., Chen Z., Liu Z. Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells. Oncotarget. 2017; 8: 15539–15552.

  49. Herst P.M., Dawson R.H., Berridge M.V. Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer. Front. Oncol. 2018; 8: 344.

  50. Jurj A., Zanoaga O., Braicu C., Lazar V., Tomuleasa C., Irimie A., Berindan-Neagoe I. A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells. Cancers (Basel). 2020; 12 (2): 298.

  51. Burt R., Dey A., Aref S., Aguiar M., Akarca A., Bailey K. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood. 2019; 134: 1415–1429.

  52. Marlein C.R., Piddock R.E., Mistry J.J., Zaitseva L., Hellmich C., Horton R.H. CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma. Cancer Res. 2019; 79: 2285–2297.

  53. Spees J.L., Olson S.D., Whitney M.J., Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. SciUSA. 2006; 103: 1283–1288.

  54. Tan A.S., Baty J., Dong L., Bezawork-Geleta A., Endaya B., Goodwin J. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 2015; 21: 81–94.

  55. Michael V. Berridge, Lanfeng Dong, Jiri Neuzil. Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer. Cancer Res. 2015; 75 (16): 3203–3208.

  56. Marlein C., Zaitseva L., Piddock R., Shafat M., Collins A., Bowles K., Rushworth S. PGC1α driven mitochondrial biogenesis within the bone marrow stromal cells of the acute myeloid leukemia micro-environment is a pre-requisite for mitochondrial transfer to leukemic blasts. Leukemia. 2017; 32: 2073–2077.

  57. Marlein C.R., Zaitseva L., Piddock R.E., Robinson S.D., Edwards D.R., Shafat M.S. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 2017; 130: 1649–1660.

  58. Bajzikova M., Kovarova J., Coelho A.R., Boukalova S., Oh S., Rohlenova K. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab. 2019; 29: 399–416.

  59. Ippolito L., Morandi A., Taddei M.L., Parri M., Comito G., Iscaro A. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene. 2019; 38: 5339–5355.

  60. Hekmatshoar Y., Nakhle J., Galloni M., Vignais M.L. The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance. Biochem. J. 2018; 475: 2305–2328.

  61. Court A.C., Le-Gatt A., Luz-Crawford P., Parra E., Aliaga-Tobar V., Bátiz L.F., Contreras R.A., Ortúzar M.I., Kurte M., Elizondo-Vega R. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020; 21: e48052.

  62. Kit O.I., Shikhlyarova A.I., Frantsiyants E.M., Neskubina I.V., Kaplieva I.V., Zhukova G.V., Trepitaki L.K., Pogorelova Y.A., Bandovkina V.A., Surikova E.I., Popov I.A., Voronina T.N., Bykadorova O.V., Serdyukova E.V. Mitochondrial therapy: direct visual assessment of the possibility of preventing myocardial infarction under chronic neurogenic pain and b16 melanoma growth in the experiment. Cardiometry. 2022; 22: 38–49.

  63. Kit O.I., Frantsiyants E.M., Shikhlyarova A.I., Neskubina I.V., Kaplieva I.V., Cheryarina N.D., Vereskunova A.A., Trepitaki L.K., Pogorelova Y.A., Bandovkina V.A., Surikova E.I., Kachesova P.S., Sheiko E.A., Kotieva I.M., Gusareva M.A., Luganskaya R.G., Bosenko E.S. Biological effects of mitochondrial therapy: preventing development of myocardial infarction and blocking metastatic aggression of B16/F10 melanoma. Cardiometry. 2022; 22: 50–55.

  64. Kit O.I., Frantsiyants E.M., Neskubina I.V., Shikhlyarova A.I., Kaplieva I.V. Mitochondrial therapy: a vision of the outlooks for treatment of main twenty-first-century diseases. Cardiometry. 2022; 22: 18–27.

  65. Kit O.I., Frantsiyants E.M., Shikhlyarova A.I., Neskubina I.V., Kaplieva I.V., Trepitaki L.K., Pogorelova Y.A., Cheryarina N.D., Vereskunova A.A., Bandovkina V.A., Surikova E.I., Maksimova N.A., Kotieva I.M., Gusareva M.A., Pozdnyakova V.V. Mitochondrial therapy of melanoma B16/F10, pathophysiological parameters of tumor regression. Cardiometry. 2022; 22: 56–61.

  66. Miliotis S., Nicolalde B., Ortega M., Yepez J., Caicedo A. Forms of extracellular mitochondria and their impact in health. Mitochondrion. 2019; 48: 16–30.

  67. Stephens O.R., Grant D., Frimel M., Wanner N., Yin M., Willard B., Erzurum S.C., Asosingh K. Characterization and origins of cell-free mitochondria in healthy murine and human blood. Mitochondrion. 2020; 54: 102–112.

  68. Dache Z.A.A., Otandault A., Tanos R., Pastor B., Meddeb R., Sanchez C., Arena G., Lasorsa L., Bennett A., Grange T. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J. 2020; 34: 3616–3630.

  69. Stier A. Human blood contains circulating cell-free mitochondria, but are they really functional? Am. J. Physiol. Metab. 2021; 320: e859–863.

 

Received April 03, 2023; accepted June 28, 2023.

 

Information about the authors

Kit Oleg Ivanovich, Doctor of Sciences (Medicine), Professor, Academician of the Russian Academy of Sciences, Director General, National Medical Research Center for Oncology, Ministry of Health of the Russian Federation. 344037, Russia, Rostov-on-Don, 14-ya Liniya St., 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-3061-6108

Frantsiyants Elena Mikhaylovna, Doctor of Sciences (Biology), Professor, Deputy Director General for Science, National Medical Research Center for Oncology, Ministry of Health of the Russian Federation. 344037, Russia, Rostov-on-Don, 14-ya Liniya St., 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0003-3618-6890

Shikhlyarova Alla Ivanovna, Doctor of Sciences (Biology), Professor, Senior Researcher, Laboratory for the Study of Malignant Tumor Pathogenesis, National Medical Research Center for Oncology, Ministry of Health of the Russian Federation. 344037, Russia, Rostov-on-Don, 14-ya Liniya St., 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-2943-7655

Neskubina Irina Valer'evna, Candidate of Sciences (Biology), National Medical Research Center for Oncology, Ministry of Health of the Russian Federation. 344037, Russia, Rostov-on-Don, 14-ya Liniya St., 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-7395-3086

 

For citation

Kit O.I., Frantsiyants E.M., Shikhlyarova A.I., Neskubina I.V. Mekhanizmy estestvennogo perenosa mitokhondriy v norme i pri onkopatologii [Mechanisms of natural mitochondrial transfer in health and in cancer]. Ul'yanovskiy mediko-biologicheskiy zhurnal. 2023; 3: 14–29. DOI: 10.34014/2227-1848-2023-3-14-29 (in Russian).

 

https://orcid.org/0000-0003-3061-6108

УДК 616-092.18;576.311.347

DOI 10.34014/2227-1848-2023-3-14-29

МЕХАНИЗМЫ ЕСТЕСТВЕННОГО ПЕРЕНОСА МИТОХОНДРИЙ В НОРМЕ И ПРИ ОНКОПАТОЛОГИИ

О.И. Кит, Е.М. Франциянц, А.И. Шихлярова, И.В. Нескубина

ФГБУ «Национальный медицинский исследовательский центр онкологии»
Министерства здравоохранения Российской Федерации, г. Ростов-на-Дону, Россия

 

В представленном обзоре обсуждаются вопросы, касающиеся динамической природы митохондрий. Освещаются механизмы, задействованные в способности этих органелл выходить за границы клеток, тем самым позволяя осуществлять их перемещение между клетками млекопитающих. Митохондрии играют ключевую роль в выработке энергии и клеточных физиологических процессах. Эти органеллы очень динамичны, постоянно меняют свою морфологию, расположение в клетке
и распределение в ответ на клеточный стресс.

В последние годы феномен переноса митохондрий привлекает значительное внимание и интерес со стороны биологов и медицинских исследователей. Межклеточный перенос митохондрий происходит различными способами, включая туннельные нанотрубки (TNT), внеклеточные везикулы (EVS) и каналы щелевых соединений (GJC). Исследования межклеточного переноса митохондрий
в физиологических и патологических условиях показали, что митохондриальный перенос обладает большим потенциалом для поддержания гомеостаза организма и регуляции патологических процессов. Недавно стало известно о высвобождении бесклеточных митохондрий в норме и патологических условиях (стресс, травмы) в кровь. Их обнаружили в виде циркулирующих внеклеточных митохондрий в крови мыши и человека. Несколько исследовательских групп разработали методы искусственного переноса / трансплантации здоровых митохондрий (AMT / T) в поврежденные клетки для восстановления клеточной функции. В этой статье рассматриваются способы, механизмы и новейшие методы межклеточного спонтанного митохондриального переноса AMT / T. Кроме того, обсуждается потенциальная ценность и механизм применения AMT / T в лечении заболеваний, в т.ч. и злокачественных новообразований.

Ключевые слова: митохондрии, злокачественные новообразования, естественный перенос митохондрий, перенос митохондрий в условиях патологии.

 

Конфликт интересов. Авторы заявляют об отсутствии конфликта интересов.

Вклад авторов

Написание текста, анализ и интерпретация данных: Франциянц Е.М.

Научное редактирование: Кит О.И., Шихлярова А.И.

Техническое редактирование, оформление библиографии: Нескубина И.В.

 

Литература

  1. Франциянц Е.М., Нескубина И.В., Черярина Н.Д., Сурикова Е.И., Шихлярова А.И., Бандовкина В.А., Немашкалова Л.А., Каплиева И.В., Трепитаки Л.К., Качесова П.С., Котиева И.М., Морозова М.И., Погорелова Ю.А. Функциональное состояние митохондрий кардиомиоцитов при злокачественном процессе на фоне коморбидной патологии в эксперименте. Южно-Российский онкологический журнал. 2021; 2 (3): 13–22.

  2. Кит О.И., Франциянц Е.М., Нескубина И.В., Сурикова Е.И., Каплиева И.В., Бандовкина В.А. Влияние варианта развития меланомы В16/F10 на содержание кальция в митохондриях различных органов самок мышей. Исследования и практика в медицине. 2021; 8 (1): 20–29.

  3. Heineman B.D., Liu X., Wu G.Y. Targeted Mitochondrial Delivery to Hepatocytes: A Review. Journal of clinical and translational hepatology. 2022; 10 (2): 321–328.

  4. Porat-Shliom N., Harding O.J., Malec L., Narayan K., Weigert R. Mitochondrial Populations Exhibit Differential Dynamic Responses to Increased Energy Demand during Exocytosis In Vivo. Science. 2019; 11: 440–449.

  5. Roy S., Kim D., Sankaramoorthy A. Mitochondrial structural changes in the pathogenesis of diabetic retinopathy. J. Clin. Med. 2019; 8 (9): 1363.

  6. Su B.K., Lee S.A., Pak K., Su Wu, Kim S.J., Woo Wu. Disbindin, associated with schizophrenia, modulates mitochondrial axonal movement in collaboration with p150 glued. Molbrain. 2021; 14 (1): 14.

  7. Valenti D., Vacca R.A., Moro L., Atlante A. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer. International journal of molecular sciences. 2021; 22 (15): 8312.

  8. Singh B., Modica-Napolitano J.S., Singh K.K. Defining the momiome: Promiscuous information transfer by mobile mitochondria and the mitochondrial genome. Semin. Cancer Biol. 2017; 47: 1–17.

  9. Shanmughapriya S., Langford D., Natarajaseenivasan K. Inter and Intracellular mitochondrial trafficking in health and disease. Ageing Res. Rev. 2020; 62: 101128.

  10. Liu Z., Sun Y., Qi Z., Cao L., Ding S. Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases. Cell & bioscience. 2022; 12 (1): 66.

  11. Liu D., Gao Y., Liu J., Huang Y., Yin J., Feng Y. Intercellular mitochondrial transfer as a means of tissue revitalization. Signal Transduct. Target. Ther. 2021; 6: 1–18.

  12. Zampieri L.X., Silva-Almeida C., Rondeau J.D., Sonveaux P. Mitochondrial Transfer in Cancer: A Comprehensive Review. Int J Mol Sci. 2021; 22 (6): 3245.

  13. Torralba D., Baixauli F., Sánchez-Madrid F. Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016; 4: 107.

  14. Paliwal S., Chaudhuri R., Agrawal A., Mohanty S. Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci. 2018; 25 (1): 31.

  15. Li H., Wang C., He T., Zhao T., Chen Y.Y., Shen Y.L. Mitochondrial transfer from bone marrow mesenchymal stem cells to motor neurons in spinal cord injury rats via gap junction. Theranostics. 2019; 9 (7): 2017–2035.

  16. Gollihue J.L., Patel S.P., Mashburn C., Eldahan K.C., Sullivan P.G., Rabchevsky A.G. Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures. J. Neurosci. Methods. 2017; 287: 1–12.

  17. Chang J.C., Hoel F., Liu K.H., Wei Y.H., Cheng F.C., Kuo S.J. Peptide-mediated delivery of donor mitochondria improves mitochondrial function and cell viability in human cybrid cells with the MELAS A3243G mutation. Sci Rep. 2017; 7 (1): 10710.

  18. Liu X., Khouri-Farah N., Wu C.H., Wu G.Y. Targeted delivery of mitochondria to the liver in rats. J. Gastroenterol. Hepatol. 2020; 35 (12): 2241–2247.

  19. Dong L.-F., Kovarova J., Bajzikova M., Bezawork-Geleta A., Svec D., Endaya B. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife. 2017; 6: e22187.

  20. Delvaeye T., Vandenabeele P., Bultynck G., Leybaert L., Krysko D.V. Therapeutic Targeting of Connexin Channels: New Views and Challenges. Trends Mol Med. 2018; 24 (12): 1036–1053.

  21. Morrison T.J., Jackson M.V., Cunningham E.K., Kissenpfennig A., McAuley D., O’Kane C. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer. Am. J. Respir. Crit. Care Med. 2017; 196: 1275–1286. DOI: https://doi.org/10.1164/rccm.201701-0170OC 

  22. Qin Y., Jiang X., Yang Q., Zhao J., Zhou Q., Zhou Y. The Functions, Methods, and Mobility of Mitochondrial Transfer Between Cells. Front. Oncol. 2021; 11: 672781.

  23. Austefjord M.W., Gerdes H.H., Wang X. Tunneling nanotubes: diversity in morphology and structure. Commun Integr Biol. 2014; 7 (1): e27934.

  24. Vignais M.L., Caicedo A., Brondello J.M. Cell connections by tunneling nanotubes: effects of mitochondrial trafficking on target cell metabolism, homeostasis, and response to therapy. Stem Cells Int. 2017; 2017: 6917941.

  25. Ljubojevic N., Henderson J.M., Zurzolo C. The ways of actin: why tunneling nanotubes are unique cell protrusions. Trends Cell Biol. 2021; 31 (2): 130–142.

  26. Yang F., Zhang Y., Liu S., Xiao J., He Y., Shao Z. Nanotube-mediated mitochondrial tunneling rescues nucleus pulposus cells from mitochondrial dysfunction and apoptosis. Oxidative cellular longevity. 2022; 2022: 3613319.

  27. Yang C., Endoh M., Tan D.Q., Nakamura-Ishizu A., Takihara Y., Matsumura T., Suda T. Mitochondria transfer from early stages of erythroblasts to their macrophage niche via tunnelling nanotubes. Br. J. Haematol. 2021; 193 (6): 1260–1274.

  28. Wang X., Gerdes H.H. Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 2015; 22 (7): 1181–1191.

  29. Abraham A., Krasnodembskaya A. Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome. Stem Cells Transl. Med. 2020; 9 (1): 28–38.

  30. Meng W., He C., Hao Y., Wang L., Li L., Zhu G. Prospects and challenges of extracellular vesicle-based drug delivery system: considering cell source. Drug Deliv. 2020; 27 (1): 585–598.

  31. Varcianna A., Myszczynska M.A., Castelli L.M., O'Neill B., Kim Y., Talbot J. Micro-RNAs secreted through astrocyte-derived extracellular vesicles cause neuronal network degeneration in C9orf72 ALS. EBioMedicine. 2019; 40: 626–635.

  32. Hayakawa K., Esposito E., Wang X., Terasaki Y., Liu Y., Xing C. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016; 535 (7613): 551–555.

  33. Nicolás-Ávila J.A., Lechuga-Vieco A.V., Esteban-Martínez L., Sánchez-Díaz M., Díaz-García E., Santiago D.J. A network of macrophages supports mitochondrial homeostasis in the heart. Cell. 2020; 183 (1): 94–109.

  34. Hough K.P., Trevor J.L., Strenkowski J.G., Wang Y., Chacko B.K., Tousif S. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018; 18: 54–64.

  35. Simeone P., Bologna G., Lanuti P., Pierdomenico L., Guagnano M.T., Pieragostino D. Extracellular vesicles as signaling mediators and disease biomarkers across biological barriers. Int. J. Mol. Sci. 2020; 21: 2514.

  36. Sansone P., Savini C., Kurelac I., Chang Q., Amato L.B., Strillacci A. Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc. Natl. Acad. Sci. USA. 2017; 114: E9066–E9075.

  37. Murray L.M.A., Krasnodembskaya A.D. Concise review: intercellular communication via organelle transfer in the biology and therapeutic applications of stem cells. Stem Cells. 2019; 37 (1): 14–25.

  38. Mohammadalipour A., Dumbali S.P., Wenzel P.L. Mitochondrial transfer and regulators of mesenchymal stromal cell function and therapeutic efficacy. Front Cell Dev Biol. 2020; 8: 603292.

  39. Senos Demarco R., Jones D.L. Mitochondrial fission regulates germ cell differentiation by suppressing ROS-mediated activation of epidermal growth factor signaling in the Drosophila larval testis. Sci. Rep. 2019; 9 (1): 19695.

  40. Alarcon-Martinez L., Villafranca-Baughman D., Quintero H., Kacerovsky J.B., Dotigny F., Murai K.K. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature. 2020; 585 (7823): 91–95.

  41. Pinto G., Saenz-de-Santa-Maria I., Chastagner P., Perthame E., Delmas C., Toulas C. Patient-derived glioblastoma stem cells transfer mitochondria through tunneling nanotubes in tumor organoids. Biochem J. 2021; 478 (1): 21–39.

  42. Maeda A., Fadeel B. Mitochondria released by cells undergoing TNF-alpha-induced necroptosis act as danger signals. Cell Death Dis. 2014; 5: e1312.

  43. Phinney D.G., Di Giuseppe M., Njah J., Sala E., Shiva S., St Croix C.M. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6: 8472.

  44. Mahrouf-Yorgov M., Augeul L., Da Silva C.C., Jourdan M., Rigolet M., Manin S. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 2017; 24 (7): 1224–1238.

  45. Sahinbegovic H., Jelinek T., Hrdinka M., Bago J.R., Turi M., Sevcikova T. Intercellular Mitochondrial Transfer in the Tumor Microenvironment. Cancers. 2020; 12: 1787.

  46. Nakahira K., Hisata S., Choi A.M. The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases. Antioxid. Redox Signal. 2015; 23: 1329–1350.

  47. Roh J.S., Sohn D.H. Damage-Associated Molecular Patterns in Inflammatory Diseases. Immune Netw. 2018; 18: e27.

  48. Lu J., Zheng X., Li F., Yu Y., Chen Z., Liu Z. Tunneling nanotubes promote intercellular mitochondria transfer followed by increased invasiveness in bladder cancer cells. Oncotarget. 2017; 8: 15539–15552.

  49. Herst P.M., Dawson R.H., Berridge M.V. Intercellular Communication in Tumor Biology: A Role for Mitochondrial Transfer. Front. Oncol. 2018; 8: 344.

  50. Jurj A., Zanoaga O., Braicu C., Lazar V., Tomuleasa C., Irimie A., Berindan-Neagoe I. A Comprehensive Picture of Extracellular Vesicles and Their Contents. Molecular Transfer to Cancer Cells. Cancers (Basel). 2020; 12 (2): 298.

  51. Burt R., Dey A., Aref S., Aguiar M., Akarca A., Bailey K. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood. 2019; 134: 1415–1429.

  52. Marlein C.R., Piddock R.E., Mistry J.J., Zaitseva L., Hellmich C., Horton R.H. CD38-Driven Mitochondrial Trafficking Promotes Bioenergetic Plasticity in Multiple Myeloma. Cancer Res. 2019; 79: 2285–2297.

  53. Spees J.L., Olson S.D., Whitney M.J., Prockop D.J. Mitochondrial transfer between cells can rescue aerobic respiration. Proc. Natl. Acad. SciUSA. 2006; 103: 1283–1288.

  54. Tan A.S., Baty J., Dong L., Bezawork-Geleta A., Endaya B., Goodwin J. Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab. 2015; 21: 81–94.

  55. Michael V. Berridge, Lanfeng Dong, Jiri Neuzil. Mitochondrial DNA in Tumor Initiation, Progression, and Metastasis: Role of Horizontal mtDNA Transfer. Cancer Res. 2015; 75 (16): 3203–3208.

  56. Marlein C., Zaitseva L., Piddock R., Shafat M., Collins A., Bowles K., Rushworth S. PGC1α driven mitochondrial biogenesis within the bone marrow stromal cells of the acute myeloid leukemia micro-environment is a pre-requisite for mitochondrial transfer to leukemic blasts. Leukemia. 2017; 32: 2073–2077.

  57. Marlein C.R., Zaitseva L., Piddock R.E., Robinson S.D., Edwards D.R., Shafat M.S. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 2017; 130: 1649–1660.

  58. Bajzikova M., Kovarova J., Coelho A.R., Boukalova S., Oh S., Rohlenova K. Reactivation of dihydroorotate dehydrogenase-driven pyrimidine biosynthesis restores tumor growth of respiration-deficient cancer cells. Cell Metab. 2019; 29: 399–416.

  59. Ippolito L., Morandi A., Taddei M.L., Parri M., Comito G., Iscaro A. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene. 2019; 38: 5339–5355.

  60. Hekmatshoar Y., Nakhle J., Galloni M., Vignais M.L. The role of metabolism and tunneling nanotube-mediated intercellular mitochondria exchange in cancer drug resistance. Biochem. J. 2018; 475: 2305–2328.

  61. Court A.C., Le-Gatt A., Luz-Crawford P., Parra E., Aliaga-Tobar V., Bátiz L.F., Contreras R.A., Ortúzar M.I., Kurte M., Elizondo-Vega R. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020; 21: e48052.

  62. Kit O.I., Shikhlyarova A.I., Frantsiyants E.M., Neskubina I.V., Kaplieva I.V., Zhukova G.V., Trepitaki L.K., Pogorelova Y.A., Bandovkina V.A., Surikova E.I., Popov I.A., Voronina T.N., Bykadorova O.V., Serdyukova E.V. Mitochondrial therapy: direct visual assessment of the possibility of preventing myocardial infarction under chronic neurogenic pain and b16 melanoma growth in the experiment. Cardiometry. 2022; 22: 38–49.

  63. Kit O.I., Frantsiyants E.M., Shikhlyarova A.I., Neskubina I.V., Kaplieva I.V., Cheryarina N.D., Vereskunova A.A., Trepitaki L.K., Pogorelova Y.A., Bandovkina V.A., Surikova E.I., Kachesova P.S., Sheiko E.A., Kotieva I.M., Gusareva M.A., Luganskaya R.G., Bosenko E.S. Biological effects of mitochondrial therapy: preventing development of myocardial infarction and blocking metastatic aggression of B16/F10 melanoma. Cardiometry. 2022; 22: 50–55.

  64. Kit O.I., Frantsiyants E.M., Neskubina I.V., Shikhlyarova A.I., Kaplieva I.V. Mitochondrial therapy: a vision of the outlooks for treatment of main twenty-first-century diseases. Cardiometry. 2022; 22: 18–27.

  65. Kit O.I., Frantsiyants E.M., Shikhlyarova A.I., Neskubina I.V., Kaplieva I.V., Trepitaki L.K., Pogorelova Y.A., Cheryarina N.D., Vereskunova A.A., Bandovkina V.A., Surikova E.I., Maksimova N.A., Kotieva I.M., Gusareva M.A., Pozdnyakova V.V. Mitochondrial therapy of melanoma B16/F10, pathophysiological parameters of tumor regression. Cardiometry. 2022; 22: 56–61.

  66. Miliotis S., Nicolalde B., Ortega M., Yepez J., Caicedo A. Forms of extracellular mitochondria and their impact in health. Mitochondrion. 2019; 48: 16–30.

  67. Stephens O.R., Grant D., Frimel M., Wanner N., Yin M., Willard B., Erzurum S.C., Asosingh K. Characterization and origins of cell-free mitochondria in healthy murine and human blood. Mitochondrion. 2020; 54: 102–112.

  68. Dache Z.A.A., Otandault A., Tanos R., Pastor B., Meddeb R., Sanchez C., Arena G., Lasorsa L., Bennett A., Grange T. Blood contains circulating cell-free respiratory competent mitochondria. FASEB J. 2020; 34: 3616–3630.

  69. Stier A. Human blood contains circulating cell-free mitochondria, but are they really functional? Am. J. Physiol. Metab. 2021; 320: e859–863.

 

Поступила в редакцию 03.04.2023; принята 28.06.2023.

 

Авторский коллектив

Кит Олег Иванович – доктор медицинских наук, профессор, академик РАН, генеральный директор, ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава России. 344037, Россия, г. Ростов-на-Дону, ул. 14-я линия, 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-3061-6108

Франциянц Елена Михайловна – доктор биологических наук, профессор, заместитель генерального директора по науке, ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава России. 344037, Россия, г. Ростов-на-Дону, ул. 14-я линия, 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: http://orcid.org/0000-0003-3618-6890

Шихлярова Алла Ивановна – доктор биологических наук, профессор, старший научный сотрудник лаборатории изучения патогенеза злокачественных опухолей, ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава России. 344037, Россия, г. Ростов-на-Дону, ул. 14-я линия, 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0003-2943-7655

Нескубина Ирина Валерьевна – кандидат биологических наук, ФГБУ «Национальный медицинский исследовательский центр онкологии» Минздрава России. 344037, Россия, г. Ростов-на-Дону, ул. 14-я линия, 63; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it., ORCID ID: https://orcid.org/0000-0002-7395-3086

 

Образец цитирования

Кит О.И., Франциянц Е.М., Шихлярова А.И., Нескубина И.В. Механизмы естественного переноса митохондрий в норме и при онкопатологии. Ульяновский медико-биологический журнал. 2023; 3: 14–29. DOI: 10.34014/2227-1848-2023-3-14-29.