The Functions, Methods, and Mobility of Mitochondrial Transfer Between Cells

Mitochondria are vital organelles in cells, regulating energy metabolism and apoptosis. Mitochondrial transcellular transfer plays a crucial role during physiological and pathological conditions, such as rescuing recipient cells from bioenergetic deficit and tumorigenesis. Studies have shown several structures that conduct transcellular transfer of mitochondria, including tunneling nanotubes (TNTs), extracellular vesicles (EVs), and Cx43 gap junctions (GJs). The intra- and intercellular transfer of mitochondria is driven by a transport complex. Mitochondrial Rho small GTPase (MIRO) may be the adaptor that connects the transport complex with mitochondria, and myosin XIX is the motor protein of the transport complex, which participates in the transcellular transport of mitochondria through TNTs. In this review, the roles of TNTs, EVs, GJs, and related transport complexes in mitochondrial transcellular transfer are discussed in detail, as well as the formation mechanisms of TNTs and EVs. This review provides the basis for the development of potential clinical therapies targeting the structures of mitochondrial transcellular transfer.

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Tunneling nanotubes, TNT, communicate glioblastoma with surrounding non-tumor astrocytes to adapt them to hypoxic and metabolic tumor conditions

Scientific Reports ◽

10.1038/s41598-021-93775-8 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Silvana Valdebenito ◽

Shaily Malik ◽

Ross Luu ◽

Olivier Loudig ◽

Megan Mitchell ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Cancer Cells ◽

Communication System ◽

Cell Communication ◽

Proper Function ◽

Tunneling Nanotubes ◽

Cancer Pathogenesis ◽

Pathological Conditions ◽

Mitochondrial Transfer

AbstractCell-to-cell communication is essential for the development and proper function of multicellular systems. We and others demonstrated that tunneling nanotubes (TNT) proliferate in several pathological conditions such as HIV, cancer, and neurodegenerative diseases. However, the nature, function, and contribution of TNT to cancer pathogenesis are poorly understood. Our analyses demonstrate that TNT structures are induced between glioblastoma (GBM) cells and surrounding non-tumor astrocytes to transfer tumor-derived mitochondria. The mitochondrial transfer mediated by TNT resulted in the adaptation of non-tumor astrocytes to tumor-like metabolism and hypoxia conditions. In conclusion, TNT are an efficient cell-to-cell communication system used by cancer cells to adapt the microenvironment to the invasive nature of the tumor.

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Melatonin reshapes the mitochondrial network and promotes intercellular mitochondrial transfer via tunneling nanotubes (TNTs) after ischemic‐like injury in hippocampal HT22 cells

Journal of Pineal Research ◽

10.1111/jpi.12747 ◽

2021 ◽

Author(s):

Maria Gemma Nasoni ◽

Silvia Carloni ◽

Barbara Canonico ◽

Sabrina Burattini ◽

Erica Cesarini ◽

...

Keyword(s):

Mitochondrial Network ◽

Tunneling Nanotubes ◽

Ht22 Cells ◽

Mitochondrial Transfer

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Mitochondrial Transfer in Cancer: A Comprehensive Review

International Journal of Molecular Sciences ◽

10.3390/ijms22063245 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3245

Author(s):

Luca X. Zampieri ◽

Catarina Silva-Almeida ◽

Justin D. Rondeau ◽

Pierre Sonveaux

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Metabolic Pathways ◽

Current Knowledge ◽

Cancer Cell Proliferation ◽

Tunneling Nanotubes ◽

Comprehensive Review ◽

Cancer Cell Death ◽

Mitochondrial Transfer ◽

Metabolic Activities

Depending on their tissue of origin, genetic and epigenetic marks and microenvironmental influences, cancer cells cover a broad range of metabolic activities that fluctuate over time and space. At the core of most metabolic pathways, mitochondria are essential organelles that participate in energy and biomass production, act as metabolic sensors, control cancer cell death, and initiate signaling pathways related to cancer cell migration, invasion, metastasis and resistance to treatments. While some mitochondrial modifications provide aggressive advantages to cancer cells, others are detrimental. This comprehensive review summarizes the current knowledge about mitochondrial transfers that can occur between cancer and nonmalignant cells. Among different mechanisms comprising gap junctions and cell-cell fusion, tunneling nanotubes are increasingly recognized as a main intercellular platform for unidirectional and bidirectional mitochondrial exchanges. Understanding their structure and functionality is an important task expected to generate new anticancer approaches aimed at interfering with gains of functions (e.g., cancer cell proliferation, migration, invasion, metastasis and chemoresistance) or damaged mitochondria elimination associated with mitochondrial transfer.

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Endothelial k-RasV12 Expression Induces Capillary Deficiency Attributable to Marked Tube Network Expansion Coupled to Reduced Pericytes and Basement Membranes

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.121.316798 ◽

2021 ◽

Author(s):

Zheying Sun ◽

Scott S. Kemp ◽

Prisca K. Lin ◽

Kalia N. Aguera ◽

George E. Davis

Keyword(s):

Protein Kinase ◽

Basement Membrane ◽

Arteriovenous Malformations ◽

Network Formation ◽

Tube Formation ◽

Small Gtpase ◽

Basement Membranes ◽

Formation Mechanisms ◽

Lumen Formation ◽

The Impact

Objective: We sought to determine how endothelial cell (EC) expression of the activating k-Ras mutation, k-RasV12, affects their ability to form lumens and tubes and interact with pericytes during capillary assembly Approach and Results: Using defined bioassays where human ECs undergo observable tubulogenesis, sprouting behavior, pericyte recruitment to EC-lined tubes, and pericyte-induced EC basement membrane deposition, we assessed the impact of EC k-RasV12 expression on these critical processes that are necessary for proper capillary network formation. This mutation, which is frequently seen in human ECs within brain arteriovenous malformations, was found to markedly accentuate EC lumen formation mechanisms, with strongly accelerated intracellular vacuole formation, vacuole fusion, and lumen expansion and with reduced sprouting behavior, leading to excessively widened tube networks compared with control ECs. These abnormal tubes demonstrate strong reductions in pericyte recruitment and pericyte-induced EC basement membranes compared with controls, with deficiencies in fibronectin, collagen type IV, and perlecan deposition. Analyses of signaling during tube formation from these k-RasV12 ECs reveals strong enhancement of Src, Pak2 (P21 [RAC1 (Rac family small GTPase 1)] activated kinase 2), b-Raf (v-raf murine sarcoma viral oncogene homolog B1), Erk (extracellular signal–related kinase), and Akt activation and increased expression of PKCε (protein kinase C epsilon), MT1-MMP (membrane-type 1 matrix metalloproteinase), acetylated tubulin and CDCP1 (CUB domain-containing protein 1; most are known EC lumen regulators). Pharmacological blockade of MT1-MMP, Src, Pak, Raf, Mek (mitogen-activated protein kinase) kinases, Cdc42 (cell division cycle 42)/Rac1, and Notch markedly interferes with lumen and tube formation from these ECs. Conclusions: Overall, this novel work demonstrates that EC expression of k-RasV12 disrupts capillary assembly due to markedly excessive lumen formation coupled with strongly reduced pericyte recruitment and basement membrane deposition, which are critical pathogenic features predisposing the vasculature to develop arteriovenous malformations.

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Human Bone Marrow Mesenchymal Stem Cells Rescue Endothelial Cells Experiencing Chemotherapy Stress by Mitochondrial Transfer Via Tunneling Nanotubes

Stem Cells and Development ◽

10.1089/scd.2018.0248 ◽

2019 ◽

Vol 28 (10) ◽

pp. 674-682 ◽

Cited By ~ 12

Author(s):

Yonghuai Feng ◽

Rongjia Zhu ◽

Jing Shen ◽

JiMin Wu ◽

Wenyi Lu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Endothelial Cells ◽

Mesenchymal Stem Cells ◽

Human Bone ◽

Human Bone Marrow ◽

Tunneling Nanotubes ◽

Mitochondrial Transfer ◽

Marrow Mesenchymal Stem Cells

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Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Response

International Journal of Molecular Sciences ◽

10.3390/ijms20236017 ◽

2019 ◽

Vol 20 (23) ◽

pp. 6017 ◽

Cited By ~ 10

Author(s):

Prospero Civita ◽

Diana M. Leite ◽

Geoffrey Pilkington

Keyword(s):

Drug Resistance ◽

Hyaluronic Acid ◽

Drug Testing ◽

Tunneling Nanotubes ◽

Mitochondrial Transfer ◽

Culture Models ◽

And Migration ◽

2D And 3D

The role of astrocytes in the glioblastoma (GBM) microenvironment is poorly understood; particularly with regard to cell invasion and drug resistance. To assess this role of astrocytes in GBMs we established an all human 2D co-culture model and a 3D hyaluronic acid-gelatin based hydrogel model (HyStem™-HP) with different ratios of GBM cells to astrocytes. A contact co-culture of fluorescently labelled GBM cells and astrocytes showed that the latter promotes tumour growth and migration of GBM cells. Notably, the presence of non-neoplastic astrocytes in direct contact, even in low amounts in co-culture, elicited drug resistance in GBM. Recent studies showed that non-neoplastic cells can transfer mitochondria along tunneling nanotubes (TNT) and rescue damaged target cancer cells. In these studies, we explored TNT formation and mitochondrial transfer using 2D and 3D in vitro co-culture models of GBM and astrocytes. TNT formation occurs in glial fibrillary acidic protein (GFAP) positive “reactive” astrocytes after 48 h co-culture and the increase of TNT formations was greater in 3D hyaluronic acid-gelatin based hydrogel models. This study shows that human astrocytes in the tumour microenvironment, both in 2D and 3D in vitro co-culture models, could form TNT connections with GBM cells. We postulate that the association on TNT delivery non-neoplastic mitochondria via a TNT connection may be related to GBM drug response as well as proliferation and migration.

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From Cell Entry to Engraftment of Exogenous Mitochondria

International Journal of Molecular Sciences ◽

10.3390/ijms21144995 ◽

2020 ◽

Vol 21 (14) ◽

pp. 4995

Author(s):

Daisuke Kami ◽

Satoshi Gojo

Keyword(s):

Gene Transfer ◽

Horizontal Gene Transfer ◽

Clinical Development ◽

Cell Entry ◽

Endosomal Escape ◽

Isolated Mitochondria ◽

Pathological Conditions ◽

Mitochondrial Transfer ◽

Environmental Materials ◽

Initial Process

Mitochondrial transfer has been recognized to play a role in a variety of processes, ranging from fertilization to cancer and neurodegenerative diseases as well as mammalian horizontal gene transfer. It is achieved through either exogeneous or intercellular mitochondrial transfer. From the viewpoint of evolution, exogeneous mitochondrial transfer is quite akin to the initial process of symbiosis between α-protobacterium and archaea, although the progeny have developed more sophisticated machinery to engulf environmental materials, including nutrients, bacteria, and viruses. A molecular-based knowledge of endocytosis, including macropinocytosis and endosomal escape involving bacteria and viruses, could provide mechanistic insights into exogeneous mitochondrial transfer. We focus on exogeneous mitochondrial transfer in this review to facilitate the clinical development of the use of isolated mitochondria to treat various pathological conditions. Several kinds of novel procedures to enhance exogeneous mitochondrial transfer have been developed and are summarized in this review.

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Mitochondrial donation in translational medicine; from imagination to reality

Journal of Translational Medicine ◽

10.1186/s12967-020-02529-z ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Hesam Saghaei Bagheri ◽

Farhad Bani ◽

Savas Tasoglu ◽

Amir Zarebkohan ◽

Reza Rahbarghazi ◽

...

Keyword(s):

Translational Medicine ◽

Specific Activity ◽

Current Knowledge ◽

Review Article ◽

Target Cells ◽

Therapeutic Effects ◽

Cellular Mechanisms ◽

Pathological Conditions ◽

Mitochondrial Transfer ◽

Mitochondrial Donation

Abstract The existence of active crosstalk between cells in a paracrine and juxtacrine manner dictates specific activity under physiological and pathological conditions. Upon juxtacrine interaction between the cells, various types of signaling molecules and organelles are regularly transmitted in response to changes in the microenvironment. To date, it has been well-established that numerous parallel cellular mechanisms participate in the mitochondrial transfer to modulate metabolic needs in the target cells. Since the conception of stem cells activity in the restoration of tissues’ function, it has been elucidated that these cells possess a unique capacity to deliver the mitochondrial package to the juxtaposed cells. The existence of mitochondrial donation potentiates the capacity of modulation in the distinct cells to achieve better therapeutic effects. This review article aims to scrutinize the current knowledge regarding the stem cell’s mitochondrial transfer capacity and their regenerative potential.

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Cx43 and Associated Cell Signaling Pathways Regulate Tunneling Nanotubes in Breast Cancer Cells

Cancers ◽

10.3390/cancers12102798 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2798

Author(s):

Alexander Tishchenko ◽

Daniel D. Azorín ◽

Laia Vidal-Brime ◽

María José Muñoz ◽

Pol Jiménez Arenas ◽

...

Keyword(s):

Breast Cancer ◽

Gap Junctions ◽

Small Molecules ◽

Cancer Cells ◽

Signaling Pathways ◽

Connexin 43 ◽

Breast Cancer Cell Lines ◽

Tunneling Nanotubes ◽

Cx43 Expression ◽

Cancer Signaling

Connexin 43 (Cx43) forms gap junctions that mediate the direct intercellular diffusion of ions and small molecules between adjacent cells. Cx43 displays both pro- and anti-tumorigenic properties, but the mechanisms underlying these characteristics are not fully understood. Tunneling nanotubes (TNTs) are long and thin membrane projections that connect cells, facilitating the exchange of not only small molecules, but also larger proteins, organelles, bacteria, and viruses. Typically, TNTs exhibit increased formation under conditions of cellular stress and are more prominent in cancer cells, where they are generally thought to be pro-metastatic and to provide growth and survival advantages. Cx43 has been described in TNTs, where it is thought to regulate small molecule diffusion through gap junctions. Here, we developed a high-fidelity CRISPR/Cas9 system to knockout (KO) Cx43. We found that the loss of Cx43 expression was associated with significantly reduced TNT length and number in breast cancer cell lines. Notably, secreted factors present in conditioned medium stimulated TNTs more potently when derived from Cx43-expressing cells than from KO cells. Moreover, TNT formation was significantly induced by the inhibition of several key cancer signaling pathways that both regulate Cx43 and are regulated by Cx43, including RhoA kinase (ROCK), protein kinase A (PKA), focal adhesion kinase (FAK), and p38. Intriguingly, the drug-induced stimulation of TNTs was more potent in Cx43 KO cells than in wild-type (WT) cells. In conclusion, this work describes a novel non-canonical role for Cx43 in regulating TNTs, identifies key cancer signaling pathways that regulate TNTs in this setting, and provides mechanistic insight into a pro-tumorigenic role of Cx43 in cancer.

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