CC BY
0South Russian Journal of Cancer. 2024. Vol. 5, No. 1. P. 60-70 https://doi.org/10.37748/2686-9039-2024-5-1-7 https://elibrary.ru/ymkxii
REVIEW
Mitochondrial transplantation: new challenges for cancer
O. I. Kit, E. M. Frantsiyants, A. I. Shikhlyarova, I. V. Neskubina 12
National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
12 neskubina.irina@mail.ru
This review discusses the uniqueness of mitochondria providing normal cellular functions and at the same time involved in many pathological conditions, and also analyzes the scientific literature to clarify the effectiveness of mitochondrial transplan- tation in cancer treatment. Being important and semi-autonomous organelles in cells, they are able to adapt their functions to the needs of the corresponding organ. The ability of mitochondria to reprogram is important for all cell types that can switch between resting and proliferation. At the same time, tumor mitochondria undergo adaptive changes to accelerate the reproduc- tion of tumor cells in an acidic and hypoxic microenvironment. According to emerging data, mitochondria can go beyond the boundaries of cells and move between the cells of the body. Intercellular transfer of mitochondria occurs naturally in humans as a normal mechanism for repairing damaged cells. The revealed physiological mitochondrial transfer has become the basis for a modern form of mitochondrial transplantation, including autologous (isogenic), allogeneic, and even xenogenic trans- plantation. Currently, exogenous healthy mitochondria are used in treatment of several carcinomas, including breast cancer, pancreatic cancer, and glioma. Investigation of the functional activity of healthy mitochondria demonstrated and confirmed the fact that female mitochondria are more efficient in suppressing tumor cell proliferation than male mitochondria. However, tissue-specific sex differences in mitochondrial morphology and oxidative capacity were described, and few studies showed functional sex differences in mitochondria during therapy. The reviewed studies report that mitochondrial transplantation can be specifically targeted to a tumor, providing evidence for changes in tumor function after mitochondrial administration. Thus, the appearance of the most interesting data on the unique functions of mitochondria indicates the obvious need for mitochondrial transplantation.
For citation: Kit O. I., Frantsiyants E. M., Shikhlyarova A. I., Neskubina I. V. Mitochondrial transplantation: new challenges for cancer. South Russian Journal of Cancer. 2024; 5(1): 60-70. https://doi.org/10.37748/2686-9039-2024-5-1-7, https://elibrary.ru/ymkxii
For correspondence: Irina V. Neskubina - Cand. Sci. (Biol.), senior researcher at the laboratory for the study of the pathogenesis of malignant tumors, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
Address: 63 14 line str., Rostov-on-Don 344037, Russian Federation E-mail: neskubina.irina@mail.ru
ORCID: https://orcid.org/0000-0002-7395-3086 SPIN: 3581-8531, AuthorID: 794688
ResearcherID: AAG-8731-2019 Scopus Author ID: 6507509066
Funding: this work was not funded
Conflict of interest: Kit O. I. has been the member of the editorial board of the South Russian Journal of Cancer since 2019, however he has no relation to the decision made upon publishing this article. The article has passed the review procedure accepted in the journal. The authors did not declare any other conflicts of interest
The article was submitted 28.02.2023; approved after reviewing 12.08.2023; accepted for publication 27.02.2024
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?????: 344037, ?????????? ?????????, ?. ??????-??-????, ??. 14 ?????, ?. 63 E-mail: neskubina.irina@mail.ru
ORCID: https://orcid.org/0000-0002-7395-3086 SPIN: 3581-8531, AuthorID: 794688
ResearcherID: AAG-8731-2019 Scopus Author ID: 6507509066
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INTRODUCTION
Mitochondria have played a fundamental role in the evolution of complex organisms. Being import- ant and semi-autonomous organelles in cells, they are able to adapt their functions to the needs of the corresponding organ. Mitochondria can reprogram their intended purpose for the desired result: for an exceptional supply of energy to maintain the func- tioning of heart muscle cells throughout life or to control metabolic processes in secreting organs, for example, to support the work of hepatocytes and the liver. The ability of mitochondria to reprogram is important for all cell types that can switch between resting and proliferation, such as stem cells and im- mune cells. Most chronic diseases are characterized by a violation of mitochondrial regulation, which has been revealed in cardiovascular diseases, metabol- ic syndrome, neurodegenerative diseases, immune system disorders and malignant neoplasms [1-7]. The purpose of this review article was to evalu- ate new possibilities in the treatment of malignant
neoplasms during mitochondrial transplantation.
Functional and dysfunctional multiplicity
of mitochondria
Malignant tumors invariably rearrange their metabolism, promoting cellular plasticity with ad- aptation to the constantly changing availability of nutrients and the acquisition of aggressive disease traits, including the ability to metastasize. Cancer metabolism has long been equated with the pre- dominant use of glycolysis by tumor cells even in the presence of oxygen, the so-called Warburg ef- fect [8]. However, it is now known that the functions of mitochondria in tumor metabolism are broader,
e. g. the use of oxidative bioenergetics, a change in the redox balance, the inclusion of multiple mecha- nisms of cell survival and retrograde expression of nuclear genes, as well as the effect on the primary and metastatic spread of a malignant tumor [9-11]. Interestingly, just like differentiated cells, mitochon- dria perform specialized functions unique to specif- ic organs and tissues. For example, mitochondria in the liver are mainly involved in biosynthetic process- es, and mitochondria in the heart or muscles main- ly produce ATP. Mitochondria in adipocytes play a crucial role in regulating adipocyte differentiation, insulin sensitivity, and adaptive thermogenesis [12].
Analysis of the mitochondrial proteome isolated from various tissues such as the brain, liver, heart and kidneys of rats showed mitochondrial hetero- geneity specializing in different functions between tissues. Abnormalities in mitochondria disrupt basic physiological functions such as ATP production, oxidative phosphorylation, reactive oxygen species (ROS) production and Ca2+ regulation, all of which are considered mitochondrial dysfunction. In addi- tion, these unique organelles, which are important for normal cellular function, can be involved in many pathological conditions. Mitochondria are present in every cell of the human body, with the exception of red blood cells - erythrocytes. The production of ATP by mitochondria leads to the formation of small amounts of potentially destructive free radicals known as reactive oxygen species (ROS). These radicals are secondary messengers in vital cellular signaling cascades for normal biological processes. However, the accumulation of byproducts of ATP production can harm the cell and provoke damage to cellular organelles, as well as disruption of met- abolic processes [13].
It is obvious that mitochondria are the most im-
portant organelles responsible for cell survival and apoptosis. Healthy mitochondria are essential for maintaining the normal functioning of cells. At the same time, accumulated research data indicates that tumor mitochondria undergo adaptive changes to accelerate the proliferation of tumor cells in an acidic and hypoxic microenvironment [14]. There is in- creasing evidence that mitochondrial metabolism and function are indispensable in oncogenesis and cancer progression, which makes mitochondria and their functions likely targets for antitumor therapy [15].
Although the mechanisms of mitochondrial reprogramming in cancer have recently received more attention, the role of organelle in this process has not been widely considered [16, 17]. In fact, the microenvironment in which the tumor grows is extremely unfavorable for mitochondria, since un- stable oxygen concentrations and oxidative radicals can disrupt the integrity of organelles, disintegrate the regulation of many mitochondrial functions and activate cellular death [18]. Therefore, the way how mitochondria cope with the loss of their "functional form" remains unclear, and the effect of substan- dard or damaged mitochondria on tumor signs has not been studied [19]
Mitochondrial movement as a basis for
mitochondrial therapy
Endosymbiotic theory suggests that mitochon- dria were once primary free-living unicellular or- ganisms that may have been absorbed by larger, probably anaerobic cellular organisms in order to use them for more efficient aerobic energy produc- tion [20]. This "adoption" and billions of years of evolution have led to the complexity of eukaryotes. The proof of this theory is that mitochondria contain their own DNA (mtDNA) in the form of ring DNA, similar to that found in bacteria, and also contains two lipid bilayers. Mitochondria, like bacteria, are equipped with an intracellular mechanism nec- essary to produce 13 of their own mitochondrial proteins, but at the same time use nuclear DNA to produce other key proteins. It is due to this endo- symbiotic origin that the internalization of mito- chondria by recipient cells is possible [21].
Emerging data show that mitochondria can tran-
scend cell boundaries, move between mammalian cells, radically challenging the concepts of intracel- lular segregation of mitochondria and inheritance of mitochondrial DNA, i. e. the mtDNA. Their sig- naling role may extend to intercellular communica- tion, showing that the mitochondrial genome and even entire mitochondria are indeed mobile and can mediate information transfer between cells. This newly discovered process of mobile transfer of mitochondria and mtDNA has been called the "momiome" to denote all "mobile functions of mi- tochondria and the mitochondrial genome" [22]. Mitochondrial intercellular transfer promotes the integration of mitochondria into the endogenous mitochondrial network of recipient cells, contrib- uting to changes in their bioenergetic status and other functional properties of recipient cells not only in vitro, but also in vivo. Moreover, transcellular transfer of mitochondrial genes can have serious consequences in the pathophysiology of mitochon- drial dysfunction [23].
It has been reported that intercellular mitochon-
drial transfer naturally occurs in humans as a nor- mal mechanism for repairing damaged cells [24, 25]. This physiological phenomenon inspired re- searchers to create a modern form of mitochondrial transplantation, including autologous (isogenic), allogeneic and even xenogenic transplantation [4, 26, 27]. Given that mitochondrial dysfunction may
be at the center of devastating pathological condi- tions, mitochondrial transfer, called mitochondrial transplantation, has high therapeutic potential in modern medicine.
Mitochondrial transplantation is an innovative strategy for the treatment of mitochondrial dys- function, which allows overcoming the limitations of agent-based therapy. Mitochondrial replace- ment, transplantation, or transfer is a new inter- vention and treatment for patients diagnosed with mitochondrial disease [28]. Mitochondrial transfer is based on the concept of targeted tRNA therapy. Treatment strategies for mitochondrial dysfunc- tion are usually divided into the following cate- gories: enhancing mitochondrial biogenesis; re- ducing dysfunctional mitochondria and replacing them with active ones; delivery or replacement of dysfunctional components; intervention in the consequences of mitochondrial dysfunction and reprogramming of the mitochondrial genome [29, 30]. It is believed that mitochondria persist in cells throughout their lives. The prerequisite for mitochondrial transfer is that the cell can perceive many different environmental signals and subse- quently absorb, transfer, process and integrate foreign material. Which signals trigger mitochon- drial transfer is of great importance for further theory and treatment. Current data have proven that mitochondrial transfer between cells is often triggered by multiple intracellular and extracellular events of the recipient cell. These events can act as "find me" or "save me" signals, recruiting the appropriate donor mitochondria to provide them to recipient cells [13].
Several in vitro studies have shown that intercel-
lular mitochondrial transfer occurs naturally. When DsRed-labeled mitochondria isolated from mesen- chymal cells (EMC) originating from the endome- trial glands of the human uterus were co-incubated with isogenic EMC for 24 hours, the accumulation of exogenous mitochondria in the cytoplasm of recipients was observed using imaging of living fluorescent cells [31]. In another study, it was also observed that xenogenic transfer of mitochondria isolated from mouse liver tissue to human cells de- void of functional mitochondria (cells p 0) restores respiratory function [32]. These results prove the possibility of treating mitochondrial diseases with mitochondrial transplantation.
In addition to the observed transfer of mitochon- dria in in vitro experiments, the possibility of intro- ducing mitochondria directly into living organisms seems relevant. The mitochondria used for injection can be autologous, allogeneic, or even xenogenic. Doulamis I. P. et al. injected allogeneic or autolo- gous mitochondria of muscle cells into damaged areas of the heart of rats with diabetes, both vari- ants of mitochondria led to the restoration of left ventricular function and a decrease in the size of infarction [33]. Mitochondria can be injected directly into the damaged area or elsewhere. For example, Lin H. S. et al. mitochondria were injected into the spleen for the treatment of ischemically damaged liver [34]. In addition, in the past, researchers more often injected mitochondria directly into the region- al ischemic zone to repair myocardial damage, and recently decided to inject mitochondria into the left coronary mouth or coronary artery [33, 35]. Local intracerebral or systemic intraarterial injection of mitochondria can significantly restore the area of cerebral infarction and the death of neuronal cells [36]. In addition, intraarterial injection or in- travascular delivery of mitochondria into blood vessels has been performed to treat acute kidney injury or lung injury [37]. A recent study has shown the existence of intact and functional mitochondria in human peripheral blood [26]. Moreover, there is much evidence that there are many mitochondrial components in the blood, such as cell-free circu- lating mtDNA, vesicles of mitochondrial origin and peptides of mitochondrial origin, and these com- ponents increase in disease [38-40]. Although the significance of their presence in the blood and their association with disease are unclear, the presence of these components demonstrates that mitochon- dria can play a signal-regulating role through circu- lation in distant cells, even if they are fragmented. Accordingly, intravascular administration of mito- chondria can be promising if we understand in ad- vance the existence of mitochondria in the blood, the biological role of mitochondrial components.
Dysfunctional dominance of malignant mitochondria and the possibility
of counteraction
The mitochondria of malignant cells play a key role in the interaction of tumor cells with the tumor microenvironment [41]. As recent scientific studies
have shown, tumors are not only composed of ma- lignant cells, they are a complex system of tumor and non-tumor cells that create symbiotic relation- ships in the tumor microenvironment, contributing to survival and resistance to chemotherapy. Malig- nant cells are able to displace entire mitochondria or some of their components, including mtDNA, cytochrome C, and formylated peptides into the tumor microenvironment [42]. They, in turn, function as damage-associated molecular patterns (DAMPs) that are released from damaged or "dying" cells and activate the innate immune system.
Elliott R. L. et al. (2012) found that mitochon- dria purified from immortalized, untransformed MCF-12A breast epithelial cells can successfully penetrate human breast cancer cell lines and sup- press them depending on the dose. Mitochondria from MCF-12A cells can also be transferred to hu- man breast cancer MCF-7 cell lines, which is ac- companied by increased sensitivity to chemother- apy with doxorubicin, abraxane or carboplatin [43]. This is the first publication concerning the transfer of mitochondria that promote apoptosis of malig- nant cells and increase sensitivity to drugs.
Accumulating research data show that tumor mi- tochondria undergo adaptive changes to accelerate the rapid proliferation of tumor cells in an acidic and hypoxic microenvironment [14]. Thus, it is assumed that the introduction of healthy mitochondria into tumor cells is highly effective in preventing tumor growth [44]. Currently, exogenous healthy mitochon- dria are used to treat several carcinomas, including breast cancer, pancreatic cancer and glioma, and excellent antitumor efficacy of healthy mitochon- dria has been shown [45-47]. At the same time, the authors, based on the obtained biochemical data, noted the fact that healthy mitochondria after mi- tochondrial transplantation can significantly reduce the ability to oxidative phosphorylation (OXPHOS) and induce apoptosis in tumor cells. However, the molecular signaling mechanism of this process re- mains unclear.
The mechanism of mitochondrial penetration, immune reactions
Intercellular mitochondrial transfer occurs through tunneling nanotubes (TNT), extracellular vesicles (EV) and cell fusion. Recently, functional- ly active mitochondria free of cells and cytoplas-
mic membrane have been observed in blood and conditioned medium for cell culture [48]. Although the role of extracellular mitochondria in intercellu- lar communication has yet to be fully understood, practical approaches aimed at transferring intact mitochondria to target cells have been developed previously.
The mechanism of mitochondrial penetration into cells may be related to macropinocytosis-mediated endocytosis, since a macropinocytosis inhibitor can prevent the internalization of mitochondria by cells. Moreover, mitochondria are considered as systemic intermediaries in intercellular communication [49]. It is also known that mitochondria can be absorbed by various cell types, as has been shown in in vitro and in vivo studies [50]. In addition, mitochondria in the blood can activate the immune system by increasing the activity of phagocytes and T cells, which can to a certain extent enhance the antitumor effect of mitochondria [51].
To date, some studies have discussed the im-
mune reactions that occur during mitochondrial transplantation - MT. Understanding their involve- ment in the effectiveness of MT would be valuable to reduce possible risks. With existing mitochon- drial disease, transplantation of mitochondria ob- tained from autologous cells is possible without inflammation and autoimmune reactions [52]. Some researchers believe that autologous mitochondrial transplantation may have more effective results. However, in some cases, including diseases asso- ciated with mitochondria, or in some of the most severe patients, isolation of their own mitochondria is impossible. On the other hand, some patients re- quire multiple series of injections. Therefore, in this regard, transplantation of heterologous mitochon- dria is inevitable [53]. The main possible problems of heterogeneous mitochondrial transplantation are immune system reactions and damage-related mo- lecular pattern (DAMP). It should be noted that in all previous studies, only one injection of mitochondria was reported. And what happens after a series of injections of mitochondria into damaged tissues? McCully J. D. et al. (2017) conducted a study to find out the behavior of the immune system after direct or indirect autogenic and allogeneic injections, sin- gle and serial injections, as well as various numbers of isolated mitochondria (1�105, 1�106 or 1�107 mitochondria). The data obtained showed that the
level of immune system profiles, including IL-1, IL-4, IL-6, IL-12, IL-18, IP-10, macrophage inflammatory protein MIP-1 a and MIP-1 � did not change. Single or serial injections of mitochondria did not show the presence of DAMP in the recipient's tissues [54]. Ramirez-Barbieri G. et al. (2019) investigated the immune response and damage-related molecular patterns (DAMPs) In mice, after single or multiple intraperitoneal injections of allogeneic mitochon- dria, it was found that serum cytokine and mtDNA levels did not increase either after autologous or after allogeneic mitochondrial injection [55].
Sex-related features of mitochondria
Mitochondria are an almost exclusive legacy of the mother in evolution, and during transplantation therapy, sex differences in the functioning of mito- chondria may occur. It was previously reported that the mitochondria of female animals (female mito- chondria) are more sensitive to stress and better adapted to combat adverse conditions, therefore, it was assumed that female mitochondria have dif- ferent activity in antitumor growth compared with the mitochondria of males [56].
A number of reports have described tissue- specific sex differences in mitochondrial morphol- ogy and oxidative capacity, while only a few studies have shown functional differences in mitochon- dria during therapy. At the same time, it has been shown that the mitochondria of women have a high- er protein content and the ability to produce ATP than in men [57]. According to the available limited data, female mitochondria have more favorable mitochondrial-nuclear communication in response to stress compared to male mitochondria [58].
Yu Z. et al. (2021) evaluated the activity of mi- tochondria isolated from female and male mice, and the results showed that female mitochondria showed higher activity and ability to produce ATP than male mitochondria. Subsequently, antitumor mitochondrial effects in a number of experiments, both in vitro and in vivo models, proved that female mitochondria have a higher efficiency of suppress- ing tumor cell proliferation than male mitochondria. The study also showed that female mitochondria can induce a more sustained stress response to gene transcription than male mitochondria in tumor cells, suggesting that female mitochondria are more sensitive to the hypoxic microenvironment of the tu-
mor than male mitochondria, and ultimately lead to a stronger antitumor effect. The authors used intact mitochondria to study their antitumor activity when administered intravenously. This study demonstrat- ed a new understanding of mitochondrial function in the development of melanoma and suggests that healthy mitochondria inhibit tumor cell proliferation by preventing transcription of tumor genes. General downregulation of genes leads to cell cycle arrest and stagnation of cell proliferation, as well as acti- vation of autophagy and apoptosis, which ultimately leads to an obvious inhibition of melanoma growth after mitochondrial transplantation therapy [59].
CONCLUSION
Today, mitochondria are much more than just the "powerhouse" of the cells. Mitochondrial trans- plantation therapy has been an active area of re- search for the treatment of diseases related to mitochondrial dysfunction, from animal studies to clinical trials. However, the specific mechanism providing antitumor activity of healthy mitochon- dria has yet to be defined. The mechanism of in- tercellular mitochondrial transfer is still partially understood and requires further research, while its targeting may provide new opportunities in the treatment of malignant neoplasms. Evidence that mitochondrial transfer can occur in a similar way in solid and hematological tumor cells further in- creases the importance of this process as a basis
for mitochondrial transplantation. In addition, the involvement of mitochondrial transfer in cancer progression and the development of chemoresis- tance may explain the still unclear mechanisms of action of some anticancer drugs. It has been proven that the therapeutic effect of mitochondrial transplantation is a potential method of treating diseases associated with mitochondria. However, there are several problems that need to be solved so that the treatment of the disease with mito- chondrial transplantation can be effectively ap- plied to humans.
Most studies emphasize that the isolation of mi- tochondria should be completed in a short time at a low temperature, since they are very sensitive, and their activity and survival are rapidly decreasing. In addition, there is currently no method for long-term storage of mitochondria, so they should be used immediately after isolation. Therefore, a protocol for the optimal method of mitochondrial isolation and storage, which maintains the integrity of mi- tochondria and ensures longer survival, should be developed to enable clinical use.
Since mitochondria are easily obtained from cul- tured cells, and the technology of mitochondrial iso- lation and preservation is becoming more mature, it is expected that large-scale mitochondrial donation centers will be established in the future. Thus, when autologous transplantation cannot be performed, it is possible to find a compatible mitochondrial donor just in time.
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Information about authors:
Oleg I. Kit - Academician at the Russian Academy of Sciences, Dr. Sci. (Med.), professor, general director, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
ORCID: https://orcid.org/0000-0003-3061-6108, SPIN: 1728-0329, AuthorID: 343182, ResearcherID: U-2241-2017, Scopus Author ID: 55994103100
Elena M. Frantsiyants - Dr. Sci. (Biol.), professor, deputy CEO for science, National Medical Research Centre for Oncology, Rostov-on-Don, Russian
Federation
ORCID: https://orcid.org/0000-0003-3618-6890, SPIN: 9427-9928, AuthorID: 462868, ResearcherID: Y-1491-2018, Scopus Author ID: 55890047700
Alla I. Shikhlyarova - Dr. Sci. (Biol.), professor, senior researcher, Laboratory of Study of Malignant Tumor Pathogenesis, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
ORCID: https://orcid.org/0000-0003-2943-7655, SPIN: 6271-0717, AuthorID: 482103, ResearcherID: Y-6275-2018, Scopus Author ID: 6507723229
Irina V. Neskubina 12 - Cand. Sci. (Biol.), senior researcher at the Laboratory for the Study of the Pathogenesis of Malignant Tumors, National Medical Research Centre for Oncology, Rostov-on-Don, Russian Federation
ORCID: https://orcid.org/0000-0002-7395-3086, SPIN: 3581-8531, AuthorID: 794688, ResearcherID: AAG-8731-2019, Scopus Author ID: 6507509066
Contribution of the authors:
Kit O. I. - scientific editing;
Frantsyants E. M. - text writing, data analysis and interpretation; Shikhlyarova A. I. - scientific editing;
Neskubina I. V. - technical editing, bibliography design.
