RESUMO
Mitochondrial dysfunction plays a vital role in growth and malignancy of tumors. In recent scenarios, mitochondrial transplantation therapy is considered as an effective method to remodel mitochondrial function in mitochondria-related diseases. However, the mechanism by which mitochondrial transplantation blocks tumor cell proliferation is still not determined. In addition, mitochondria are maternal inheritance in evolution, and mitochondria obtained from genders exhibit differences in mitochondrial activity. Therefore, the study indicates the inhibitory effect of mitochondria from different genders on hepatocellular carcinoma and explores the molecular mechanism. The results reveal that the healthy mitochondria can retard the proliferation of the hepatocellular carcinoma cells in vitro and in vivo through arresting cell cycle and inducing apoptosis. The molecular mechanism suggests that mitochondrial transplantation therapy can decrease aerobic glycolysis, and down-regulate the expression of cycle-related proteins while up-regulate apoptosis-related proteins in tumor cells. In addition, the antitumor activity of mitochondria from female mice (F-Mito) is relatively higher than that of mitochondria from male mice (M-Mito), which would be related to the evidence that the F-Mito process higher activity than the M-Mito. This study clarifies the mechanism of exogenous mitochondria inhibiting the proliferation of hepatocellular carcinoma and contributes a new biotechnology for therapy of mitochondria-related diseases from different genders.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Apoptose , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Masculino , Camundongos , Mitocôndrias/metabolismoRESUMO
Today mitochondria are considered much more than a energy plant in cells. Mitochondrial transplantation therapy has been an active research area for treating mitochondria-associated diseases from animal studies to clinical trials. However, the specific mechanism involved in the anti-tumor activity of healthy mitochondria remain to be characterized. Here we investigate the signal mechanism and gender difference of mitochondrial transplantation therapy against malignant melanoma. In the study, we administrated intact mitochondria extracted from mouse livers respectively to the mice bearing malignantly subcutaneous and metastatic melanoma, and identified the signal mechanism responsible for the mitochondrial treatment through transcriptomic analysis. Meanwhile, the efficiency of female mitochondria and male mitochondria was compared in the cultured melanoma cells and transplanted melanoma in mice. The results suggested that the mitochondria significantly inhibited the tumor cell proliferation in vitro through cell cycle arrest and induction of cell apoptosis. In the melanoma-bearing mice, the mitochondria retard the tumor growth and lung migration, and the transcriptomic analysis indicated that general chromosome silencing was strongly associated with the mitochondria against melanoma after the mitochondrial transplantation on the metastasis melanoma. Moreover, the anti-tumor activity of mitochondria from female animals was more efficient in comparison to the males, and the female mitochondria could probably induce more persuasive mitochondria-nuclear communication than the mitochondria from male mice. The study identifies the anti-tumor mechanism of the mitochondrial transplantation therapy, and provides a novel insight into the effect of mitochondria from different gender.
Assuntos
Melanoma , Mitocôndrias Hepáticas , Metástase Neoplásica , Fatores Sexuais , Transplante/métodos , Animais , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patologia , Melanoma/terapia , Potencial da Membrana Mitocondrial , Camundongos , Mitocôndrias Hepáticas/fisiologia , Mitocôndrias Hepáticas/transplante , Metástase Neoplásica/patologia , Metástase Neoplásica/terapia , Resultado do TratamentoRESUMO
Changes in mitochondrial structure and function are mostly responsible for aging and age-related features. Whether healthy mitochondria could prevent aging is, however, unclear. Here we intravenously injected the mitochondria isolated from young mice into aged mice and investigated the mitotherapy on biochemistry metabolism and animal behaviors. The results showed that heterozygous mitochondrial DNA (mtDNA) of both aged and young mouse coexisted in tissues of aged mice after mitochondrial administration, and meanwhile, ATP content in tissues increased while reactive oxygen species (ROS) level reduced. Besides, the mitotherapy significantly improved cognitive and motor performance of aged mice. Our study, at the first report in aged animals, not only provides a useful approach to study mitochondrial function associated with aging, but also a new insight into anti-aging through mitotherapy.
Assuntos
Cognição/fisiologia , DNA Mitocondrial/metabolismo , Animais , DNA Mitocondrial/genética , DNA Mitocondrial/ultraestrutura , Imunofluorescência , Aprendizagem/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Transmissão , Mitocôndrias/metabolismo , Mitocôndrias/ultraestrutura , Teste do Labirinto Aquático de Morris , Estresse Oxidativo/genética , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Tumor mitochondria alter their functions to reprogram cell metabolism and then allow tumor cells to rapidly proliferate in the hypoxic and acidic microenvironment. However, roles of normal mitochondria played in tumor progression are still unclear. Here we investigate the normal mitochondrial effect on abnormal metabolism of tumors, and to clarify why the mitochondria have to undergo functional changes in the tumor growth. The mitochondria isolated from healthy mouse livers were intravenously injected into melanoma model mice with lung metastasis, then the tumor growth, animal survival and associated metabolic changes were studied. The results reveal that the mitochondria significantly retard tumor growth and increase survival days of animals. The anti-tumor effect of the mitochondria is related to interfering the tumor cell metabolisms, such as reducing glycolysis and producing an oxidative intracellular environment, all of which are not suitable for tumor cell proliferation. In addition, the mitochondria increases cell apoptosis, necrosis, and mitophagy. These effects are more efficient with the mitochondria isolated from young mouse livers than those from aged mice. Our study not only provides a valuable approach to invest mitochondrial function associated with tumor growth but also offer new insight into tumor therapy through interfering the tumor cell metabolism by healthy mitochondria.