Horizontal transfer of mitochondria from the tumour microenvironment to cancer cells to support proliferation and enhance tumour progression has been shown for various types of cancer in recent years. Glioblastoma, the most aggressive adult brain tumour, has proven to be no exception when it comes to dynamic intercellular mitochondrial movement, as shown in this study using an orthotopic tumour model of respiration-deficient glioblastoma cells. Although confirmed mitochondrial transfer was shown to facilitate tumour progression in glioblastoma, we decided to investigate whether the related electron transport chain recovery is necessary for tumour formation in the brain. Based on experiments using time-resolved analysis of tumour formation by glioblastoma cells depleted of their mitochondrial DNA, we conclude that functional mitochondrial respiration is essential for glioblastoma growth in vivo, because it is needed to support coenzyme Q redox cycling for de novo pyrimidine biosynthesis controlled by respiration-linked dihydroorotate dehydrogenase enzyme activity. We also demonstrate here that astrocytes are key mitochondrial donors in this model.

• MeSH
• Astrocytes metabolism   pathology   MeSH
• Cell Respiration MeSH
• Dihydroorotate Dehydrogenase MeSH
• Glioblastoma * pathology   metabolism   genetics   MeSH
• Humans MeSH
• DNA, Mitochondrial genetics   MeSH
• Mitochondria * metabolism   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Brain Neoplasms * pathology   metabolism   genetics   MeSH
• Oxidoreductases Acting on CH-CH Group Donors metabolism   MeSH
• Cell Proliferation MeSH
• Electron Transport MeSH
• Ubiquinone metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Dihydroorotate Dehydrogenase MeSH
• DNA, Mitochondrial MeSH
• Oxidoreductases Acting on CH-CH Group Donors MeSH
• Ubiquinone MeSH

Intercellular mitochondria transfer is an evolutionarily conserved process in which one cell delivers some of their mitochondria to another cell in the absence of cell division. This process has diverse functions depending on the cell types involved and physiological or disease context. Although mitochondria transfer was first shown to provide metabolic support to acceptor cells, recent studies have revealed diverse functions of mitochondria transfer, including, but not limited to, the maintenance of mitochondria quality of the donor cell and the regulation of tissue homeostasis and remodelling. Many mitochondria-transfer mechanisms have been described using a variety of names, generating confusion about mitochondria transfer biology. Furthermore, several therapeutic approaches involving mitochondria-transfer biology have emerged, including mitochondria transplantation and cellular engineering using isolated mitochondria. In this Consensus Statement, we define relevant terminology and propose a nomenclature framework to describe mitochondria transfer and transplantation as a foundation for further development by the community as this dynamic field of research continues to evolve.

• MeSH
• Humans MeSH
• Mitochondria * transplantation   metabolism   physiology   MeSH
• Terminology as Topic * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.

• MeSH
• Energy Metabolism MeSH
• Phylogeny MeSH
• Mitochondria * metabolism   MeSH
• Neoplasms * genetics   metabolism   MeSH
• Mammals MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comment MeSH
• Research Support, Non-U.S. Gov't MeSH

Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form of ATP is dispensable for cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for tumor cell migration, invasion and metastasis. The spatial positioning and transport of mitochondria involves Miro proteins from a subfamily of small GTPases, localized in outer mitochondrial membrane. Miro proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor proteins. In this review, we discuss the function of Miro proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro proteins in nanotube-mediated transfer as well as in cancer cell migration and metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.

• Keywords
• Miro, cancer, intercellular transfer, metastasis, migration, mitochondria, respiration,
• Publication type
• Journal Article MeSH
• Review MeSH

Intracellular trafficking of organelles driven by molecular motors underlies essential cellular processes. Mitochondria, the powerhouses of the cell, are one of the major cargoes of molecular motors. Efficient distribution of mitochondria ensures cellular fitness while defects in this process contribute to severe pathologies, such as neurodegenerative diseases. Reconstitution of the mitochondrial microtubule-based transport in vitro in a bottom-up approach provides a powerful tool to investigate the mitochondrial trafficking machinery in a controlled environment in the absence of complex intracellular interactions. In this chapter, we describe the procedures for achieving such reconstitution of mitochondrial transport.

• Keywords
• Adaptor proteins, Interference reflection microscopy, Kinesin-1, Mitochondria, Molecular motors, Motility assay, TIRF microscopy, TRAK,
• MeSH
• Biological Transport MeSH
• Kinesins * MeSH
• Microtubules * metabolism   MeSH
• Mitochondria metabolism   MeSH
• Organelles MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Kinesins * MeSH

Tunnelling nanotubes (TNTs) are an emerging route of long-range intercellular communication that mediate cell-to-cell exchange of cargo and organelles and contribute to maintaining cellular homeostasis by balancing diverse cellular stresses. Besides their role in intercellular communication, TNTs are implicated in several ways in health and disease. Transfer of pathogenic molecules or structures via TNTs can promote the progression of neurodegenerative diseases, cancer malignancy, and the spread of viral infection. Additionally, TNTs contribute to acquiring resistance to cancer therapy, probably via their ability to rescue cells by ameliorating various pathological stresses, such as oxidative stress, reactive oxygen species (ROS), mitochondrial dysfunction, and apoptotic stress. Moreover, mesenchymal stem cells play a crucial role in the rejuvenation of targeted cells with mitochondrial heteroplasmy and oxidative stress by transferring healthy mitochondria through TNTs. Recent research has focussed on uncovering the key regulatory molecules involved in the biogenesis of TNTs. However further work will be required to provide detailed understanding of TNT regulation. In this review, we discuss possible associations with Rho GTPases linked to oxidative stress and apoptotic signals in biogenesis pathways of TNTs and summarize how intercellular trafficking of cargo and organelles, including mitochondria, via TNTs plays a crucial role in disease progression and also in rejuvenation/therapy.

• Keywords
• Apoptosis, Cellular stress, Chemotherapy resistance, Intercellular transfer, Mesenchymal stem cells, Mitochondrial homeostasis, Reactive oxygen species (ROS), Rejuvenation,
• MeSH
• Humans MeSH
• Cell Communication * MeSH
• Mitochondria metabolism   MeSH
• Neoplasms metabolism   pathology   MeSH
• Neurodegenerative Diseases metabolism   pathology   MeSH
• Organelles metabolism   MeSH
• Oxidative Stress * MeSH
• Reactive Oxygen Species metabolism   MeSH
• rho GTP-Binding Proteins physiology   MeSH
• Virus Diseases metabolism   pathology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Reactive Oxygen Species MeSH
• rho GTP-Binding Proteins MeSH

Tumor cells without mitochondrial (mt) DNA (ρ0 cells) are auxotrophic for uridine, and their growth is supported by pyruvate. While ATP synthesis in ρ0 cells relies on glycolysis, they fail to form tumors unless they acquire mitochondria from stromal cells. Mitochondrial acquisition restores respiration that is essential for de novo pyrimidine biosynthesis and for mitochondrial ATP production. The physiological processes that underpin intercellular mitochondrial transfer to tumor cells lacking mtDNA and the metabolic remodeling and restored tumorigenic properties of cells that acquire mitochondria are not well understood. Here, we investigated the changes in mitochondrial and nuclear gene expression that accompany mtDNA deletion and acquisition in metastatic murine 4T1 breast cancer cells. Loss of mitochondrial gene expression in 4T1ρ0 cells was restored in cells recovered from subcutaneous tumors that grew from 4T1ρ0 cells following acquisition of mtDNA from host cells. In contrast, the expression of most nuclear genes that encode respiratory complex subunits and mitochondrial ribosomal subunits was not greatly affected by loss of mtDNA, indicating ineffective mitochondria-to-nucleus communication systems for these nuclear genes. Further, analysis of nuclear genes whose expression was compromised in 4T1ρ0 cells showed that immune- and stress-related genes were the most highly differentially expressed, representing over 70% of those with greater than 16-fold higher expression in 4T1 compared with 4T1ρ0 cells. The monocyte recruiting chemokine, Ccl2, and Psmb8, a subunit of the immunoproteasome that generates MHCI-binding peptides, were the most highly differentially expressed. Early monocyte/macrophage recruitment into the tumor mass was compromised in 4T1ρ0 cells but recovered before mtDNA could be detected. Taken together, our results show that mitochondrial acquisition by tumor cells without mtDNA results in bioenergetic remodeling and re-expression of genes involved in immune function and stress adaptation.

• Keywords
• 4T1 model, breast cancer, gene expression, mitochondrial DNA, tumor macrophages,
• Publication type
• Journal Article MeSH

Mitochondria are essential cellular organelles, controlling multiple signalling pathways critical for cell survival and cell death. Increasing evidence suggests that mitochondrial metabolism and functions are indispensable in tumorigenesis and cancer progression, rendering mitochondria and mitochondrial functions as plausible targets for anti-cancer therapeutics. In this review, we summarised the major strategies of selective targeting of mitochondria and their functions to combat cancer, including targeting mitochondrial metabolism, the electron transport chain and tricarboxylic acid cycle, mitochondrial redox signalling pathways, and ROS homeostasis. We highlight that delivering anti-cancer drugs into mitochondria exhibits enormous potential for future cancer therapeutic strategies, with a great advantage of potentially overcoming drug resistance. Mitocans, exemplified by mitochondrially targeted vitamin E succinate and tamoxifen (MitoTam), selectively target cancer cell mitochondria and efficiently kill multiple types of cancer cells by disrupting mitochondrial function, with MitoTam currently undergoing a clinical trial.

• Keywords
• anti-cancer strategy, drug delivery, mitocans, mitochondrial targeting,
• MeSH
• Drug Resistance, Neoplasm drug effects   MeSH
• Molecular Targeted Therapy MeSH
• Citric Acid Cycle drug effects   MeSH
• Electron Transport Chain Complex Proteins drug effects   metabolism   MeSH
• Clinical Trials as Topic MeSH
• Humans MeSH
• Mitochondria drug effects   metabolism   MeSH
• Neoplasms drug therapy   metabolism   MeSH
• Oxidation-Reduction drug effects   MeSH
• Disease Progression MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Gene Expression Regulation, Neoplastic drug effects   MeSH
• Signal Transduction drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Electron Transport Chain Complex Proteins MeSH
• Antineoplastic Agents MeSH

Cell-to-cell communication is a fundamental process in every multicellular organism. In addition to membrane-bound and released factors, the sharing of cytosolic components represents a new, poorly explored signaling route. An extraordinary example of this communication channel is the direct transport of mitochondria between cells. In this review, we discuss how intercellular mitochondrial transfer can be used by cancer cells to sustain their high metabolic requirements and promote drug resistance and describe relevant molecular players in the context of current and future cancer therapy.

• Keywords
• cancer, mitochondria, mitochondrial transfer, tumor microenvironment, tunneling nanotubes,
• Publication type
• Journal Article MeSH
• Review MeSH

Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential cellular processes. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases robustness of kinesin-1 stepping on crowded microtubule surfaces. Interaction with TRAK1 i) facilitates kinesin-1 navigation around obstacles, ii) increases the probability of kinesin-1 passing through cohesive islands of tau and iii) increases the run length of kinesin-1 in cell lysate. We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. Furthermore, TRAK1 enables mitochondrial transport in vitro. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.

• MeSH
• Adaptor Proteins, Vesicular Transport genetics   isolation & purification   metabolism   MeSH
• Microscopy, Fluorescence MeSH
• Kinesins genetics   isolation & purification   metabolism   MeSH
• Luminescent Proteins genetics   metabolism   MeSH
• Microtubules metabolism   MeSH
• Mitochondria metabolism   MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• tau Proteins genetics   metabolism   MeSH
• Recombinant Proteins genetics   metabolism   MeSH
• Intrinsically Disordered Proteins genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adaptor Proteins, Vesicular Transport MeSH
• KIF5B protein, human MeSH Browser
• Kinesins MeSH
• Luminescent Proteins MeSH
• tau Proteins MeSH
• Recombinant Proteins MeSH
• TRAK1 protein, human MeSH Browser
• Intrinsically Disordered Proteins MeSH