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
• lidé MeSH
• mitochondrie * metabolismus   MeSH
• terminologie jako téma * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy 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
• energetický metabolismus MeSH
• fylogeneze MeSH
• mitochondrie * metabolismus   MeSH
• nádory * genetika   metabolismus   MeSH
• savci MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• komentáře MeSH
• práce podpořená grantem 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.

• Klíčová slova
• Miro, cancer, intercellular transfer, metastasis, migration, mitochondria, respiration,
• Publikační typ
• časopisecké články MeSH
• přehledy 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.

• Klíčová slova
• Adaptor proteins, Interference reflection microscopy, Kinesin-1, Mitochondria, Molecular motors, Motility assay, TIRF microscopy, TRAK,
• MeSH
• biologický transport MeSH
• kineziny * MeSH
• mikrotubuly * metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• organely MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kineziny * 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.

• Klíčová slova
• Apoptosis, Cellular stress, Chemotherapy resistance, Intercellular transfer, Mesenchymal stem cells, Mitochondrial homeostasis, Reactive oxygen species (ROS), Rejuvenation,
• MeSH
• lidé MeSH
• mezibuněčná komunikace * MeSH
• mitochondrie metabolismus   MeSH
• nádory metabolismus   patologie   MeSH
• neurodegenerativní nemoci metabolismus   patologie   MeSH
• organely metabolismus   MeSH
• oxidační stres * MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Rho proteiny vázající GTP fyziologie   MeSH
• virové nemoci metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• reaktivní formy kyslíku MeSH
• Rho proteiny vázající GTP 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.

• Klíčová slova
• 4T1 model, breast cancer, gene expression, mitochondrial DNA, tumor macrophages,
• Publikační typ
• časopisecké články 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.

• Klíčová slova
• anti-cancer strategy, drug delivery, mitocans, mitochondrial targeting,
• MeSH
• chemorezistence účinky léků   MeSH
• cílená molekulární terapie MeSH
• citrátový cyklus účinky léků   MeSH
• elektronový transportní řetězec účinky léků   metabolismus   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mitochondrie účinky léků   metabolismus   MeSH
• nádory farmakoterapie   metabolismus   MeSH
• oxidace-redukce účinky léků   MeSH
• progrese nemoci MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• elektronový transportní řetězec MeSH
• protinádorové látky 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.

• Klíčová slova
• cancer, mitochondria, mitochondrial transfer, tumor microenvironment, tunneling nanotubes,
• Publikační typ
• časopisecké články MeSH
• přehledy 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
• adaptorové proteiny vezikulární transportní genetika   izolace a purifikace   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• kineziny genetika   izolace a purifikace   metabolismus   MeSH
• luminescentní proteiny genetika   metabolismus   MeSH
• mikrotubuly metabolismus   MeSH
• mitochondrie metabolismus   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• proteiny tau genetika   metabolismus   MeSH
• rekombinantní proteiny genetika   metabolismus   MeSH
• vnitřně neuspořádané proteiny genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny vezikulární transportní MeSH
• KIF5B protein, human MeSH Prohlížeč
• kineziny MeSH
• luminescentní proteiny MeSH
• proteiny tau MeSH
• rekombinantní proteiny MeSH
• TRAK1 protein, human MeSH Prohlížeč
• vnitřně neuspořádané proteiny MeSH

The mitochondrion has emerged as a promising therapeutic target for novel cancer treatments because of its essential role in tumorigenesis and resistance to chemotherapy. Previously, we described a natural compound, 10-((2,5-dihydroxybenzoyl)oxy)decyl) triphenylphosphonium bromide (GA-TPP+C10), with a hydroquinone scaffold that selectively targets the mitochondria of breast cancer (BC) cells by binding to the triphenylphosphonium group as a chemical chaperone; however, the mechanism of action remains unclear. In this work, we showed that GA-TPP+C10 causes time-dependent complex inhibition of the mitochondrial bioenergetics of BC cells, characterized by (1) an initial phase of mitochondrial uptake with an uncoupling effect of oxidative phosphorylation, as previously reported, (2) inhibition of Complex I-dependent respiration, and (3) a late phase of mitochondrial accumulation with inhibition of α-ketoglutarate dehydrogenase complex (αKGDHC) activity. These events led to cell cycle arrest in the G1 phase and cell death at 24 and 48 h of exposure, and the cells were rescued by the addition of the cell-penetrating metabolic intermediates l-aspartic acid β-methyl ester (mAsp) and dimethyl α-ketoglutarate (dm-KG). In addition, this unexpected blocking of mitochondrial function triggered metabolic remodeling toward glycolysis, AMPK activation, increased expression of proliferator-activated receptor gamma coactivator 1-alpha (pgc1α) and electron transport chain (ETC) component-related genes encoded by mitochondrial DNA and downregulation of the uncoupling proteins ucp3 and ucp4, suggesting an AMPK-dependent prosurvival adaptive response in cancer cells. Consistent with this finding, we showed that inhibition of mitochondrial translation with doxycycline, a broad-spectrum antibiotic that inhibits the 28 S subunit of the mitochondrial ribosome, in the presence of GA-TPP+C10 significantly reduces the mt-CO1 and VDAC protein levels and the FCCP-stimulated maximal electron flux and promotes selective and synergistic cytotoxic effects on BC cells at 24 h of treatment. Based on our results, we propose that this combined strategy based on blockage of the adaptive response induced by mitochondrial bioenergetic inhibition may have therapeutic relevance in BC.

• Klíčová slova
• decyl polyhydroxybenzoate triphenylphosphonium derivatives, doxycycline, inhibition of alpha-ketoglutarate dehydrogenase complex, inhibition of the electron transport chain, mitochondrial ribosome inhibition, mitochondrially targeted,
• MeSH
• apoptóza účinky léků   MeSH
• doxycyklin farmakologie   MeSH
• gentisáty chemie   farmakologie   MeSH
• heterocyklické sloučeniny chemie   farmakologie   MeSH
• ketoglutarátdehydrogenasový komplex antagonisté a inhibitory   genetika   MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• lidé MeSH
• mitochondrie účinky léků   patologie   MeSH
• nádory prsu farmakoterapie   genetika   patologie   MeSH
• organofosforové sloučeniny chemie   farmakologie   MeSH
• oxidativní fosforylace účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• proteinkinasy genetika   MeSH
• proteosyntéza účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• ribozomy účinky léků   MeSH
• synergismus léků MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2,5-dihydroxybenzoic acid MeSH Prohlížeč
• doxycyklin MeSH
• gentisáty MeSH
• heterocyklické sloučeniny MeSH
• ketoglutarátdehydrogenasový komplex MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• organofosforové sloučeniny MeSH
• proteinkinasy MeSH
• protinádorové látky MeSH
• tris(o-phenylenedioxy)cyclotriphosphazene MeSH Prohlížeč