Mitochondria of T Lymphocytes Promote Anti-Pulmonary Tumor Immune Response.

Background: B-cell lymphoma 2 (Bcl-2), a protein involved in apoptosis, has been proven to have carcinogenic potential and is well documented. With the recent advancement in optical technology, it has become possible to observe subcellular organelles such as mitochondria in real-time without the need for staining. Consequently, we have examined the movement of mitochondria in cancer cells, correlating it with the regulation of Bcl-2. Methods: Using a tomographic microscope, which can detect the internal structure of cells, we observed lung tumor cells. Cells were exposed to a laser beam (λ = 520 nm) inclined at 45°, and holographic images were recorded up to a depth of 30 µm of reconstruction. Results: Intriguingly, lung tumor cells rapidly expelled mitochondria upon the attachment of Bcl-2 or B-cell lymphoma extra-large (Bcl-xL) inhibitors. On the other hand, we observed that tumor cells hijack mitochondria from T cells. The hijacked mitochondria were not immediately linked to tumor cell death, but they played a role in assisting granzyme B-induced tumor cell death. Due to lower levels of Bcl-2 and Bcl-xL on the mitochondria of T cells compared to lung tumor cells, immune cells depleted of Bcl-2 and Bcl-xL were co-cultured with the tumor cells. Conclusions: As a result, a more effective tumor cell death induced by granzyme B was observed. Additionally, further enhanced anticancer immune response was observed in vivo. Together, we show that modified mitochondria of T cells can provide potential novel strategies towards tumor cell death.

High-Resolution Microscopic Characterization of Tunneling Nanotubes in Living U87 MG and LN229 Glioblastoma Cells.

Tunneling nanotubes (TNTs) are fine, nanometer-sized membrane connections between distant cells that provide an efficient communication tool for cellular organization. TNTs are thought to play a critical role in cellular behavior, particularly in cancer cells. The treatment of aggressive cancers such as glioblastoma remains challenging due to their high potential for developing therapy resistance, high infiltration rates, uncontrolled cell growth, and other aggressive features. A better understanding of the cellular organization via cellular communication through TNTs could help to find new therapeutic approaches. In this study, we investigate the properties of TNTs in two glioblastoma cell lines, U87 MG and LN229, including measurements of their diameter by high-resolution live-cell stimulated emission depletion (STED) microscopy and an analysis of their length, morphology, lifetime, and formation by live-cell confocal microscopy. In addition, we discuss how these fine compounds can ideally be studied microscopically. In particular, we show which membrane-labeling method is suitable for studying TNTs in glioblastoma cells and demonstrate that live-cell studies should be preferred to explore the role of TNTs in cellular behavior. Our observations on TNT formation in glioblastoma cells suggest that TNTs could be involved in cell migration and serve as guidance.

Tunneling nanotube-transmitted mechanical signal and its cellular response.

Tunneling nanotubes (TNTs) are elastic tubular structures that physically link cells, facilitating the intercellular transfer of organelles, chemical signals, and electrical signals. Despite TNTs serving as a multifunctional pathway for cell-cell communication, the transmission of mechanical signals through TNTs and the response of TNT-connected cells to these forces remain unexplored. In this study, external mechanical forces were applied to induce TNT bending between rat kidney (NRK) cells using micromanipulation. These forces, transmitted via TNTs, induced reduced curvature of the actin cortex and increased membrane tension at the TNT-connected sites. Additionally, TNT bending results in an elevation of intracellular calcium levels in TNT-connected cells, a response attenuated by gadolinium ions, a non-selective mechanosensitive calcium channel blocker. The degree of TNT deflection positively correlated with decreased actin cortex curvature and increased calcium levels. Furthermore, stretching TNT due to the separation of TNT-connected cells resulted in decreased actin cortex curvature and increased intracellular calcium in TNT-connected cells. The levels of these cellular responses depended on the length changes of TNTs. Moreover, TNT connections influence cell migration by regulating cell rotation, which involves the activation of mechanosensitive calcium channels. In conclusion, our study revealed the transmission of mechanical signals through TNTs and the subsequent responses of TNT-connected cells, highlighting a previously unrecognized communication function of TNTs. This research provides valuable insights into the role of TNTs in long-distance intercellular mechanical signaling.

Mitochondrial transfer from cancer-associated fibroblasts increases migration in aggressive breast cancer.

Cancer-associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which can impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs), which allow for the exchange of cargo between cell types. CAF mitochondria are an integral cargo component and are sufficient to increase the 3D migration of cancer cells. This cargo transfer results in an increase in mitochondrial ATP production in cancer cells, whereas it has a negligible impact on glycolytic ATP production. Manually increasing mitochondrial oxidative phosphorylation (OXPHOS) by providing extra substrates for OXPHOS fails to enhance cancer cell migration unless glycolysis is maintained at a constant level. Together, these data indicate that tumor-stromal cell crosstalk via TNTs and the associated metabolic symbiosis is a finely controlled mechanism by which tumor cells co-opt their microenvironment to promote cancer progression and may become a potential therapeutic target.

Lethal effects of mitochondria via microfluidics.

Tumor cells can respond to therapeutic agents by morphologic alternations including formation of tunneling nanotubes. Using tomographic microscope, which can detect the internal structure of cells, we found that mitochondria within breast tumor cells migrate to an adjacent tumor cell through a tunneling nanotube. To investigate the relationship between mitochondria and tunneling nanotubes, mitochondria were passed through a microfluidic device that mimick tunneling nanotubes. Mitochondria, through the microfluidic device, released endonuclease G (Endo G) into adjacent tumor cells, which we referred to herein as unsealed mitochondria. Although unsealed mitochondria did not induce cell death by themselves, they induced apoptosis of tumor cells in response to caspase-3. Importantly, Endo G-depleted mitochondria were ineffective as lethal agents. Moreover, unsealed mitochondria had synergistic apoptotic effects with doxorubicin in further increasing tumor cell death. Thus, we show that the mitochondria of microfluidics can provide novel strategies toward tumor cell death.

Protein-activated and FRET enhanced excited-state intermolecular proton transfer fluorescent probes for high-resolution imaging of cilia and tunneling nanotubes in live cells.

Excited-state intermolecular proton transfer (inter-ESPT) fluorescent probes responsive to specific bioactive molecules should be greatly promising for protein sensing, DNA mutation simulating and cellular process regulating. However, the inter-ESPT molecules are recessive ESPT fluorophores, which need the assistance of other molecules with both hydrogen-bond accepting and donating abilities to turn on the tautomeric fluorescence. Valid design strategies to create powerful inter-ESPT fluorescent probes are poorly developed, particularly for proteins as targets. We recently reported a unique supramolecular strategy to trigger the inter-ESPT process based on the probe-protein recognition by H-bonding and to image protein-based subcellular structures in live cells. Herein, we found that our inter-ESPT probes (inter-ESPT-01) bearing a 2-amino-3-cyanopyridine scaffold can anchor proteins and light up the "invisible" ESPT state, so as to image the proteins or the protein-based subcellular organelles. More importantly, the inter-ESPT emission of inter-ESPT-01 can be significantly enhanced by the FRET process between amino and imino tautomers, endowing the inter-ESPT-01 probes with super-bright tautomeric fluorescence. The expressed proteins Ecallantide and MarTX were selected as the models to light up the inter-ESPT fluorescence of the probes and revealed that the inter-ESPT process can be triggered by the specific probe-protein recognition events. In the use of the super-bright inter-ESPT fluorescence, not only the proteins, but also the protein-based cilia and tunneling nanotubes (TNTs) can be specifically visualized in living cancer cells. Furthermore, such recognition-driven strategy allows us to construct a unique inter-ESPT probe to track and image specific endogenous proteins in live cells, highlighting the potential of inter-ESPT fluorogens as novel intelligent biomaterials.

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma.

The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs.

Mechanical properties of tunneling nanotube and its mechanical stability in human embryonic kidney cells.

Tunneling nanotubes (TNTs) are thin membrane tubular structures that interconnect physically separated cells. Growing evidence indicates that TNTs play unique roles in various diseases by facilitating intercellular transfer of signaling and organelles, suggesting TNTs as a potential target for disease treatment. The efficiency of TNT-dependent communication is largely determined by the number of TNTs between cells. Though TNTs are physically fragile structures, the mechanical properties of TNTs and the determinants of their mechanical stability are still unclear. Here, using atomic force microscope (AFM) and microfluidic techniques, we investigated the mechanical behavior and abundance of TNTs in human embryonic kidney (HEK293) cells upon the application of forces. AFM measurements demonstrate that TNTs are elastic structures with an apparent spring constant of 79.1 ± 16.2 pN/µm. The stiffness and membrane tension of TNTs increase by length. TNTs that elongate slower than 0.5 µm/min display higher mechanical stability, due to the growth rate of F-actin inside TNTs being limited at 0.26 µm/min. Importantly, by disturbing the cytoskeleton, membrane, or adhesion proteins of TNTs, we found that F-actin and cadherin connection dominantly determines the tensile strength and flexural strength of TNTs respectively. It may provide new clues for screening TNT-interfering drugs that alter the stability of TNTs.

Shrimp miR-965 transfers tumoricidal mitochondria.

BACKGROUND: Micro RNA of Marsupenaeus japonicas has been known to promote apoptosis of tumor cells. However, the detailed mechanisms are not well understood. RESULTS: Using tomographic microscope, which can detect the internal structure of cells, we observed breast tumor cells following treatment of the miRNA. Intriguingly, we found that mitochondria migrate to an adjacent tumor cells through a tunneling nanotube. To recapitulate this process, we engineered a microfluidic device through which mitochondria were transferred. We show that this mitochondrial transfer process released endonuclease G (Endo G) into tumor cells, which we referred to herein as unsealed mitochondria. Importantly, Endo G depleted mitochondria alone did not have tumoricidal effects. Moreover, unsealed mitochondria had synergistic apoptotic effects with subtoxic dose of doxorubicin thereby mitigating cardiotoxicity. CONCLUSIONS: Together, we show that the mitochondrial transfer through microfluidics can provide potential novel strategies towards tumor cell death.

Effects of the media conditioned by various macrophage subtypes derived from THP-1 cells on tunneling nanotube formation in pancreatic cancer cells.

BACKGROUND: Tunneling nanotubes (TNTs) are special membrane structures for intercellular communications. Vital cargoes (such as mitochondria) could be delivered from healthy cells to rescue damaged ones through TNTs. The TNTs could be utilized for the purpose of systematic delivery of therapeutic agents between cells. However, there are insufficient studies on the controlled enhancement of TNT formations. The purpose of this study is to understand how macrophages influence the TNT formation in cancer cells. RESULTS: Here we compared the capabilities of inducing TNTs in human pancreatic cancer cells (PANC-1) of the media conditioned by M0, M1 and M2 macrophages derived from THP-1 cells. The M0 and M1 macrophage conditioned media promoted TNT formation. Using a focused ion beam to cut through a TNT, we observed tunnel-like structures inside dense cytoskeletons with scanning electron microscopy. The TNT formation correlated with raised motility, invasion, and epithelial-mesenchymal transition in the PANC-1 cells. Mitochondria and lysosomes were also found to be transported in the TNTs. CONCLUSIONS: These results suggest that TNT formation could be one of the responses to the immune stress in pancreatic cancer cells caused by M0 and M1 macrophages. This finding is valuable for the development of macrophage-targeting cancer therapy.

Mesenchymal Stromal Cell Mitochondrial Transfer as a Cell Rescue Strategy in Regenerative Medicine: A Review of Evidence in Preclinical Models.

Mesenchymal stromal cells (MSC) have excellent clinical potential and numerous properties that ease its clinical translation. Mitochondria play a crucial role in energy metabolism, essential for cellular activities, such as proliferation, differentiation, and migration. However, mitochondrial dysfunction can occur due to diseases and pathological conditions. Research on mitochondrial transfer from MSCs to recipient cells has gained prominence. Numerous studies have demonstrated that mitochondrial transfer led to increased adenosine triphosphate (ATP) production, recovered mitochondrial bioenergetics, and rescued injured cells from apoptosis. However, the complex mechanisms that lead to mitochondrial transfer from healthy MSCs to damaged cells remain under investigation, and the factors contributing to mitochondrial bioenergetics recovery in recipient cells remain largely ambiguous. Therefore, this review demonstrates an overview of recent findings in preclinical studies reporting MSC mitochondrial transfer, comprised of information on cell sources, recipient cells, dosage, route of administration, mechanism of transfer, pathological conditions, and therapeutic effects. Further to the above, this research discusses the potential challenges of this therapy in its clinical settings and suggestions to overcome its challenges.

Cytoneme-like protrusion formation induced by LAR is promoted by receptor dimerization.

Actin-based protrusions called cytonemes are reported to function in cell communication by supporting events such as morphogen gradient establishment and pattern formation. Despite the crucial roles of cytonemes in cell signaling, the molecular mechanism for cytoneme establishment remains elusive. In this study, we showed that the leukocyte common antigen-related (LAR) receptor protein tyrosine phosphatase plays an important role in cytoneme-like protrusion formation. Overexpression of LAR in HEK293T cells induced the formation of actin-based protrusions, some of which exceeded 200 µm in length and displayed a complex morphology with branches. Upon focusing on the regulation of LAR dimerization or clustering and the resulting regulatory effects on LAR phosphatase activity, we found that longer and more branched protrusions were formed when LAR dimerization was artificially induced and when heparan sulfate was applied. Interestingly, although the truncated form of LAR lacking phosphatase-related domains promoted protrusion formation, the phosphatase-inactive forms did not show clear changes, suggesting that LAR dimerization triggers the formation of cytoneme-like protrusions in a phosphatase-independent manner. Our results thus emphasize the importance of LAR and its dimerization in cell signaling. This article has an associated First Person interview with the first author of the paper.

Stromal Cells Serve Drug Resistance for Multiple Myeloma via Mitochondrial Transfer: A Study on Primary Myeloma and Stromal Cells.

Recently, it has become evident that mitochondrial transfer (MT) plays a crucial role in the acquisition of cancer drug resistance in many hematologic malignancies; however, for multiple myeloma, there is a need to generate novel data to better understand this mechanism. Here, we show that primary myeloma cells (MMs) respond to an increasing concentration of chemotherapeutic drugs with an increase in the acquisition of mitochondria from autologous bone marrow stromal cells (BM-MSCs), whereupon survival and adenosine triphosphate levels of MMs increase, while the mitochondrial superoxide levels decrease in MMs. These changes are proportional to the amount of incorporated BM-MSC-derived mitochondria and to the concentration of the used drug, but seem independent from the type and mechanism of action of chemotherapeutics. In parallel, BM-MSCs also incorporate an increasing amount of MM cell-derived mitochondria accompanied by an elevation of superoxide levels. Using the therapeutic antibodies Daratumumab, Isatuximab, or Elotuzumab, no similar effect was observed regarding the MT. Our research shows that MT occurs via tunneling nanotubes and partial cell fusion with extreme increases under the influence of chemotherapeutic drugs, but its inhibition is limited. However, the supportive effect of stromal cells can be effectively avoided by influencing the metabolism of myeloma cells with the concomitant use of chemotherapeutic agents and an inhibitor of oxidative phosphorylation.

Inhibition of Tunneling Nanotubes between Cancer Cell and the Endothelium Alters the Metastatic Phenotype.

The interaction of tumor cells with blood vessels is one of the key steps during cancer metastasis. Metastatic cancer cells exhibit phenotypic state changes during this interaction: (1) they form tunneling nanotubes (TNTs) with endothelial cells, which act as a conduit for intercellular communication; and (2) metastatic cancer cells change in order to acquire an elongated phenotype, instead of the classical cellular aggregates or mammosphere-like structures, which it forms in three-dimensional cultures. Here, we demonstrate mechanistically that a siRNA-based knockdown of the exocyst complex protein Sec3 inhibits TNT formation. Furthermore, a set of pharmacological inhibitors for Rho GTPase-exocyst complex-mediated cytoskeletal remodeling is introduced, which inhibits TNT formation, and induces the reversal of the more invasive phenotype of cancer cell (spindle-like) into a less invasive phenotype (cellular aggregates or mammosphere). Our results offer mechanistic insights into this nanoscale communication and shift of phenotypic state during cancer-endothelial interactions.

Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-ß aggregates.

BACKGROUND: Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aß) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aß/αSYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear. METHODS: The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aß pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aß and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized "close-culture" chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space. RESULTS: Our data show that intracellular deposits of αSYN and Aß are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the "close-culture" chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte. CONCLUSIONS: Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aß/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.

Stem cell-derived mitochondria transplantation: A promising therapy for mitochondrial encephalomyopathy.

Mitochondrial encephalomyopathies are disorders caused by mitochondrial and nuclear DNA mutations which affect the nervous and muscular systems. Current therapies for mitochondrial encephalomyopathies are inadequate and mostly palliative. However, stem cell-derived mitochondria transplantation has been demonstrated to play an key part in metabolic rescue, which offers great promise for mitochondrial encephalomyopathies. Here, we summarize the present status of stem cell therapy for mitochondrial encephalomyopathy and discuss mitochondrial transfer routes and the protection mechanisms of stem cells. We also identify and summarize future perspectives and challenges for the treatment of these intractable disorders based on the concept of mitochondrial transfer from stem cells.

Endolysosomal Mesoporous Silica Nanoparticle Trafficking along Microtubular Highways.

This study examines intra- and intercellular trafficking of mesoporous silica nanoparticles along microtubular highways, with an emphasis on intercellular bridges connecting interphase and telophase cells. The study of nanoparticle trafficking within and between cells during all phases of the cell cycle is relevant to payload destination and dilution, and impacts delivery of therapeutic or diagnostic agents. Super-resolution stochastic optical reconstruction and sub-airy unit image acquisition, the latter combined with Huygens deconvolution microscopy, enable single nanoparticle and microtubule resolution. Combined structural and functional data provide enhanced details on biological processes, with an example of mitotic inheritance during cancer cell trivision.

Mechanism of human umbilical cord mesenchymal stem cells alleviating ischemia-reperfusion injury of hepatocytes through mitochondrial transfer / 器官移植

Objective To explore the mechanism of human umbilical cord mesenchymal stem cell (HUC-MSC) alleviating ischemia-reperfusion injury (IRI) of liver cells through mitochondrial transfer. Methods Normal human liver cell line L02 was divided into the blank control group, oxygen-glucose deprivation (OGD) group, experimental control group, and L02 and HUC-MSC co-culture group (L02+HUC-MSC group). L02+HUC-MSC group was further divided into 10:1 co-culture subgroup (group A), 4:1 co-culture subgroup (group B), 2:1 co-culture subgroup (group C), 1:1co-culture subgroup (group D) and 1:2 co-culture subgroup (group E) according to different co-culture ratio of L02 and HUC-MSC. The apoptosis rate and relative reactive oxygen species (ROS) level of L02 cells were detected by flow cytometry. The MitoTracker positive rate of L02 cells was detected by flow cytometry. The mitochondrial transfer from HUC-MSC to L02 cells was observed by laser confocal microscope. Results The apoptosis rate and relative ROS level of L02 cells in the OGD group were significantly higher than those in the blank control group (both P < 0.05). Compared with the OGD group, the apoptosis rates of L02 cells in group B, C, D and E were significantly decreased (all P < 0.05), and the relative ROS level of L02 cells in group E was significantly declined (P < 0.05). The MitoTracker positive rate of L02 cells did not significantly differ between group A and experimental control group (P>0.05), whereas the MitoTracker positive rates of L02 cells in group B, C, D and E were significantly higher than that in the experimental control group in a concentration-dependent manner (all P < 0.05). Under the laser confocal microscope, mitochondrial transfer fromHUC-MSC to L02 cells could be observed through tunneling nanotube (TNT). Conclusions HUC-MSC may alleviate cell apoptosis and reduce ROS level of liver cells after IRI via direct mitochondrial transfer between cells.

Myosin X.

Myosin X (Myo10), an actin-based molecular motor, induces filopodia formation and controls cell migration in vitro. In the 25 years since Myo10 was first identified, it has been implicated in several different functions in different cell types including phagocytosis in macrophages, axon outgrowth in neurons, cell-cell adhesion in epithelial and endothelial cells, podosome formation in osteoclasts, spindle-pole positioning in meiosis and mitosis of cultured cells, migration of melanocytes and cranial neural crest cells, and invadopodia formation in cancer cells. Recently, the availability of Myo10-knockout (Myo10KO) mice has allowed for tremendous progress toward understanding the biological function of Myo10 in vivo.In this chapter, I address the structure of the Myo10 gene; the molecular structure of Myo10 protein with its multiple domains, e.g., PH, MyTH4, and FERM domains; the regulation of actin structures induced in cells by Myo10; the expression and function of Myo10 in vitro and in vivo; and the role of Myo10 in cancer. Previous reviews on Myo10 include Divito MM, Cheney RE, (Myosins: a superfamily of molecular motors chapter 14 MYOSIN X. In: Proteins and cell regulation, vol 7. Springer, Dordrecht, 2008) and Kerber ML, Cheney RE (J Cell Sci 124:3733-3741).

Intracellular and Intercellular Mitochondrial Dynamics in Parkinson's Disease.

The appearance of alpha-synuclein-positive inclusion bodies (Lewy bodies) and the loss of catecholaminergic neurons are the primary pathological hallmarks of Parkinson's disease (PD). However, the dysfunction of mitochondria has long been recognized as a key component in the progression of the disease. Dysfunctional mitochondria can in turn lead to dysregulation of calcium homeostasis and, especially in dopaminergic neurons, raised mean intracellular calcium concentration. As calcium binding to alpha-synuclein is one of the important triggers of alpha-synuclein aggregation, mitochondrial dysfunction will promote inclusion body formation and disease progression. Increased reactive oxygen species (ROS) resulting from inefficiencies in the electron transport chain also contribute to the formation of alpha-synuclein aggregates and neuronal loss. Recent studies have also highlighted defects in mitochondrial clearance that lead to the accumulation of depolarized mitochondria. Transaxonal and intracytoplasmic translocation of mitochondria along the microtubule cytoskeleton may also be affected in diseased neurons. Furthermore, nanotube-mediated intercellular transfer of mitochondria has recently been reported between different cell types and may have relevance to the spread of PD pathology between adjacent brain regions. In the current review, the contributions of both intracellular and intercellular mitochondrial dynamics to the etiology of PD will be discussed.