bims-mitrat 2024-02-11 papers

bims-mitrat

Biomed News

on Mitochondrial transplantation and transfer

Issue of 2024–02–11
six papers selected by
Gökhan Burçin Kubat, Gulhane Health Sciences Institute

Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.
Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.
Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.
Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.
Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.
Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).

Front Endocrinol (Lausanne). 2023 ;14 1346441

Mitochondrial transfer - a novel promising approach for the treatment of metabolic diseases.

Ruijing Chen, Jun Chen.

  Metabolic disorders remain a major global health concern in the 21st century, with increasing incidence and prevalence. Mitochondria play a critical role in cellular energy production, calcium homeostasis, signal transduction, and apoptosis. Under physiological conditions, mitochondrial transfer plays a crucial role in tissue homeostasis and development. Mitochondrial dysfunction has been implicated in the pathogenesis of metabolic disorders. Numerous studies have demonstrated that mitochondria can be transferred from stem cells to pathologically injured cells, leading to mitochondrial functional restoration. Compared to cell therapy, mitochondrial transplantation has lower immunogenicity, making exogenous transplantation of healthy mitochondria a promising therapeutic approach for treating diseases, particularly metabolic disorders. This review summarizes the association between metabolic disorders and mitochondria, the mechanisms of mitochondrial transfer, and the therapeutic potential of mitochondrial transfer for metabolic disorders. We hope this review provides novel insights into targeted mitochondrial therapy for metabolic disorders.

Keywords:  metabolic diseases; mitochondria; mitochondrial transfer; therapy; transplantation

DOI:  https://doi.org/10.3389/fendo.2023.1346441
Cells. 2024 Jan 23. pii: 204. [Epub ahead of print]13(3):

Prospective Approach to Deciphering the Impact of Intercellular Mitochondrial Transfer from Human Neural Stem Cells and Brain Tumor-Initiating Cells to Neighboring Astrocytes.

Jerusha Boyineni, Jason Michael Wood, Aditya Ravindra, Ethan Boley, Sarah E Donohue, Marcelo Bento Soares, Sergey Malchenko.

  The communication between neural stem cells (NSCs) and surrounding astrocytes is essential for the homeostasis of the NSC niche. Intercellular mitochondrial transfer, a unique communication system that utilizes the formation of tunneling nanotubes for targeted mitochondrial transfer between donor and recipient cells, has recently been identified in a wide range of cell types. Intercellular mitochondrial transfer has also been observed between different types of cancer stem cells (CSCs) and their neighboring cells, including brain CSCs and astrocytes. CSC mitochondrial transfer significantly enhances overall tumor progression by reprogramming neighboring cells. Despite the urgent need to investigate this newly identified phenomenon, mitochondrial transfer in the central nervous system remains largely uncharacterized. In this study, we found evidence of intercellular mitochondrial transfer from human NSCs and from brain CSCs, also known as brain tumor-initiating cells (BTICs), to astrocytes in co-culture experiments. Both NSC and BTIC mitochondria triggered similar transcriptome changes upon transplantation into the recipient astrocytes. In contrast to NSCs, the transplanted mitochondria from BTICs had a significant proliferative effect on the recipient astrocytes. This study forms the basis for mechanistically deciphering the impact of intercellular mitochondrial transfer on recipient astrocytes, which will potentially provide us with new insights into the mechanisms of mitochondrial retrograde signaling.

Keywords:  astrocytes; cancer stem cells; intercellular mitochondrial transfer; neural stem cells

DOI:  https://doi.org/10.3390/cells13030204
Int J Mol Sci. 2024 Feb 03. pii: 1857. [Epub ahead of print]25(3):

Endothelial Mitochondria Transfer to Melanoma Induces M2-Type Macrophage Polarization and Promotes Tumor Growth by the Nrf2/HO-1-Mediated Pathway.

Fu-Chen Kuo, Hsin-Yi Tsai, Bi-Ling Cheng, Kuen-Jang Tsai, Ping-Chen Chen, Yaw-Bin Huang, Chung-Jung Liu, Deng-Chyang Wu, Meng-Chieh Wu, Bin Huang, Ming-Wei Lin.

  Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor's phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Keywords:  M2-type macrophage; Nrf2; endothelial cells; melanoma; mitochondrial transplantation; tumor growth; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25031857
bioRxiv. 2024 Jan 27. pii: 2024.01.24.577036. [Epub ahead of print]

Mitochondrial Transplantation promotes protective effector and memory CD4 + T cell response during Mycobacterium tuberculosis infection and diminishes exhaustion and senescence in elderly CD4 + T cells.

Colwyn A Headley, Shalini Gautam, Angelica Olmo-Fontanez, Andreu Garcia-Vilanova, Varun Dwivedi, Alyssa Schami, Susan Weintraub, Philip S Tsao, Jordi B Torrelles, Joanne Turner.

Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis ( M.tb ), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4 + T cell response, is central to host immunity against M.tb . Chronic infections, such as M.tb , as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4 + T cell differentiation and function using aged mouse models and human CD4 + T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4 + T cells promoted the generation of protective effector and memory CD4 + T cells during M.tb infection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4 + T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.

DOI: https://doi.org/10.1101/2024.01.24.577036
Eur J Pharmacol. 2024 Feb 03. pii: S0014-2999(24)00056-6. [Epub ahead of print] 176368

Zinc remodels mitochondrial network through SIRT3/Mfn2-dependent mitochondrial transfer in ameliorating spinal cord injury.

Hui Guo, Li-Qing Chen, Zhi-Ru Zou, Shuai Cheng, Yu Hu, Liang Mao, He Tian, Xi-Fan Mei.

  Spinal cord injury (SCI) is a traumatic neuropathic condition that results in motor, sensory and autonomic dysfunction. Mitochondrial dysfunction caused by primary trauma is one of the critical pathogenic mechanisms. Moderate levels of zinc have antioxidant effects, promote neurogenesis and immune responses. Zinc normalises mitochondrial morphology in neurons after SCI. However, how zinc protects mitochondria within neurons is unknown. In the study, we used transwell culture, Western blot, Quantitative Real-time Polymerase Chain Reaction (QRT-PCR), ATP content detection, reactive oxygen species (ROS) activity assay, flow cytometry and immunostaining to investigate the relationship between zinc-treated microglia and injured neurons through animal and cell experiments. We found that zinc promotes mitochondrial transfer from microglia to neurons after SCI through Sirtuin 3 (SIRT3) regulation of Mitofusin 2 protein (Mfn2). It can rescue mitochondria in damaged neurons and inhibit oxidative stress, increase ATP levels and promote neuronal survival. Therefore, it can improve the recovery of motor function in SCI mice. In conclusion, our work reveals a potential mechanism to describe the communication between microglia and neurons after SCI, which may provide a new idea for future therapeutic approaches to SCI.

Keywords:  Mfn2; Mitochondrial network; Mitochondrial transfer; SIRT3; Zinc

DOI:  https://doi.org/10.1016/j.ejphar.2024.176368
J Pharm Sci. 2024 Feb 05. pii: S0022-3549(24)00041-8. [Epub ahead of print]

Activation of mitochondrial oxygen consumption rate by delivering coenzyme Q10 to mitochondria of rat skeletal muscle cell (L6).

Itsumi Sato, Mitsue Hibino, Atsuhito Takeda, Hideyoshi Harashima, Yuma Yamada.

  Numerous mitochondria are present in skeletal muscle cells. Muscle disease and aging impair mitochondrial functioning in the skeletal muscle. However, there have been few reports of therapeutic intervention via drug delivery to mitochondria owing to methodological difficulties. We surmised that mitochondrial activation is associated with improved skeletal muscle function. In this study, we attempted to activate the mitochondrial respiratory capacity in rat skeletal muscle cells (L6 cells) by delivering Coenzyme Q10 (CoQ10), a mitochondrial functional activator, to mitochondria using MITO-Porter, a nanoparticle that facilitates mitochondria-targeted drug delivery. Cellular uptake was confirmed by measuring the amount of fluorescence-modified MITO-Porter taken up by cells using flow cytometry. Intracellular dynamics of MITO-Porter was observed using confocal laser scanning microscopy. Mitochondrial function was assessed by measuring the mitochondrial oxygen consumption rate using an extracellular flux analyzer. The results indicated MITO-Porter-assisted delivery of CoQ10 to the mitochondria activated mitochondrial respiratory capacity in L6 cells. We believe that our results indicate the possibility of skeletal muscle therapy using mitochondrial drug delivery.

Keywords:  Drug delivery system; Lipid Nanoparticle (LNP); Liposome; Microfluidics; Muscle; Nanoparticle; Nanotechnology

DOI:  https://doi.org/10.1016/j.xphs.2024.01.020