• cancer
• immunity
• mesenchymal stem/stromal cells MSCs
• mitochondrial transfer
• regeneration

• adoptive transfer
• cancer
• immunotherapy
• mitochondrial DNA
• reactive oxygen species

• Animals
• Mice
• Reactive Oxygen Species/metabolism
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• DNA, Mitochondrial/genetics
• DNA, Mitochondrial/metabolism
• Mice, Inbred C57BL
• Oxidative Phosphorylation
• Mitochondria/metabolism
• Signal Transduction
• Disease Progression
• Heart Transplantation

• RO1CA259635 HHS | NIH | NCI | Division of Cancer Epidemiology and Genetics (DCEG)
• R01 AG078814 NIA NIH HHS
• P30 CA062203 NCI NIH HHS
• RO1AG078814 HHS | NIH | National Institute on Aging (NIA)
• P30CA062203 HHS | NIH | National Cancer Institute (NCI)
• R01 CA259635 NCI NIH HHS

• Cardiolipin
• Cardiomyopathy
• Electron transport chain
• Mitochondrial DNA
• Mitochondrial disease

• Humans
• Heart Failure
• Mitochondrial Diseases/genetics
• Mitochondrial Diseases/metabolism
• DNA, Mitochondrial/genetics
• DNA, Mitochondrial/metabolism
• Cardiomyopathies/genetics
• Mutation

Metabolic diseases, including obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD), are rising in both incidence and prevalence and remain a major global health and socioeconomic burden in the twenty-first century. Despite an increasing understanding of these diseases, the lack of effective treatments remains an ongoing challenge. Mitochondria are key players in intracellular energy production, calcium homeostasis, signaling, and apoptosis. Emerging evidence shows that mitochondrial dysfunction participates in the pathogeneses of metabolic diseases. Exogenous supplementation with healthy mitochondria is emerging as a promising therapeutic approach to treating these diseases. This article reviews recent advances in the use of mitochondrial transplantation therapy (MRT) in such treatment.

• Diabetes
• Extracellular vesicles
• Mitochondrial transfer
• Nonalcoholic fatty liver disease
• Obesity

Mitochondrial dysfunctions play a pivotal role in cerebral ischemia-reperfusion (I/R) injury. Although mitochondrial transplantation has been recently explored for the treatment of cerebral I/R injury, the underlying mechanisms and fate of transplanted mitochondria are still poorly understood.

Mitochondrial morphology and function were assessed by fluorescent staining, electron microscopy, JC-1, PCR, mitochondrial stress testing, and metabolomics. Therapeutic effects of mitochondria were evaluated by cell viability, reactive oxygen species (ROS), and apoptosis levels in a cellular hypoxia-reoxygenation model. Rat middle cerebral artery occlusion model was applied to assess the mitochondrial therapy in vivo. Transcriptomics was performed to explore the underlying mechanisms. Mitochondrial fate tracking was implemented by a variety of fluorescent labeling methods.

Neuro-2a (N2a) cell-derived mitochondria had higher mitochondrial membrane potential, more active oxidative respiration capacity, and less mitochondrial DNA copy number. Exogenous mitochondrial transplantation increased cellular viability in an oxygen-dependent manner, decreased ROS and apoptosis levels, improved neurobehavioral deficits, and reduced infarct size. Transcriptomic data showed that the differential gene enrichment pathways are associated with metabolism, especially lipid metabolism. Mitochondrial tracking indicated specific parts of the exogenous mitochondria fused with the mitochondria of the host cell, and others were incorporated into lysosomes. This process occurred at the beginning of internalization and its efficiency is related to intercellular connection.

Mitochondrial transplantation may attenuate cerebral I/R injury. The mechanism may be related to mitochondrial component separation, altering cellular metabolism, reducing ROS, and apoptosis in an oxygen-dependent manner. The way of isolated mitochondrial transfer into the cell may be related to intercellular connection.

• infection
• innate immunity
• mitochondrial DNA

• Unrelated donor transplant
• acute graft-vs-host disease
• mitochondria
• outcomes
• transplant

• Haplotypes
• Hematopoietic Stem Cell Transplantation
• Humans
• Leukocytes, Mononuclear
• Mitochondria
• Pilot Projects
• Unrelated Donors

• P30 CA077598 NCI NIH HHS
• R01 CA196754 NCI NIH HHS
• U24 CA076518 NCI NIH HHS

• cell fusion
• extracellular vesicles
• isolated mitochondria
• mitochondria donation
• mitochondria transplantation
• tunneling nanotubes

• ATP8
• autoimmune disease
• complex V
• conplastic mice
• immunometabolism
• metabolomics
• mitochondria
• mt-Atp8
• mtDNA polymorphisms
• propionate
• short chain fatty acids
• skin inflammation

• Animals
• Cells, Cultured
• Cytokines/metabolism
• DNA, Mitochondrial/genetics
• Epidermolysis Bullosa Acquisita/genetics
• Epidermolysis Bullosa Acquisita/metabolism
• Lymphocytes/metabolism
• Mice
• Mice, Inbred C57BL
• Mitochondria, Liver/genetics
• Mitochondria, Liver/metabolism
• Mitochondrial Proton-Translocating ATPases/genetics
• Polymorphism, Single Nucleotide

• Cell Nucleus/metabolism
• DNA, Mitochondrial/genetics
• DNA, Mitochondrial/metabolism
• Eukaryotic Cells
• Mitochondria/genetics

• P30 DK079626 NIDDK NIH HHS
• R01 HL103859 NHLBI NIH HHS
• T32 HL007918 NHLBI NIH HHS

Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora of different pattern recognition receptors and innate immune responses, including cGAS‐STING, TLR9 and inflammasome formation leading to, among others, robust type I interferon responses. In this Review, we discuss how mtDNA can be released from the mitochondria, the various inflammatory pathways triggered by mtDNA release and its myriad biological consequences for health and disease.

• cell death
• immunity
• inflammation
• mitochondria
• mtDNA

• Chronic fatigue syndrome
• Endotoxin tolerance
• Inflammation
• Mitochondria
• Myalgic encephalomyelitis
• Oxidative and nitrosative stress

• Fatigue Syndrome, Chronic/diagnosis
• Fatigue Syndrome, Chronic/immunology
• Humans
• Inflammation/immunology
• Inflammation/metabolism
• Mitochondria/immunology
• Mitochondria/metabolism
• Neuroimaging/methods
• Oxidation-Reduction
• Oxidative Stress/physiology

• Imperial College London

• brain aging
• cellular senescence
• development
• immune cells
• inflammation
• neurodegeneration

• Allogenic SAMP1 mice
• Cytoplasmic transfer
• Mitochondrial DNA
• Tumor suppression

While several studies have confirmed a link between mitochondrial DNA (mtDNA) mutations and cancer cell metastasis, much debate remains regarding the nature of the alternations in mtDNA leading to this effect. Meanwhile, the mitochondrial unfolded protein response (UPR^mt) has gained much attention in recent years, with most studies of this pathway focusing on its role in aging. However, the UPR^mt has also been studied in the context of cancer. More recent work suggests that rather than a single mutation or alternation, specific combinatorial mtDNA landscapes able to activate the UPR^mt may be those that are selected by metastatic cells, while mtDNA landscapes unable to activate the UPR^mt do not. This review aims at offering an overview of the confusing literature on mtDNA mutations and metastasis and the more recent work on the UPR^mt in this setting.

• breast cancer
• metastasis
• mitochondrial DNA
• mitochondrial unfolded protein response
• oxidative stress

The PH-BEACH-WD40 (PBW) protein family members play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive-Beige-like Anchor (LRBA) is a PBW protein whose immune function remains elusive. Here we show that LRBA-null mice are viable, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone-marrow grafts. Further, we demonstrate that LRBA-null Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of IFN-γ by cytokines remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where GvHD is primed or initiated, and consistent with this LRBA-null mice also demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses and thus represents a unique and novel molecular target in transplant immunology.

Mitochondria regulate multiple cell processes, including calcium signaling, apoptosis and cell metabolism. Mitochondria contain their own circular genome encoding selected subunits of the oxidative phosphorylation complexes. Recent findings reveal that, in addition to being maternally inherited, mitochondria can traverse cell boundaries and thus be horizontally transferred between cells. Although, the physiological relevance of this phenomenon is still under debate, mitochondria uptake rescues mitochondrial respiration defects in recipient cells and regulates signaling, proliferation or chemotherapy resistance in vitro and in vivo. In this review, we outline the pathophysiological consequences of horizontal mitochondrial transfer and offer a perspective on the cellular and molecular mechanisms mediating their intercellular transmission, including tunneling nanotubes, extracellular vesicles, cellular fusion, and GAP junctions. The physiological relevance of mitochondrial transfer and the potential therapeutic application of this exchange for treating mitochondrial-related diseases are discussed.

• DAMPs
• communication
• exosomes
• extracellular vesicles
• horizontal genetic transfer
• inflammation
• mitochondrial diseases
• tunneling nanotubes

There are two types of human pluripotent stem cells: Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), both of which launched themselves on clinical trials after having taken measures to overcome problems: Blocking rejections by immunosuppressants regarding ESCs and minimizing the risk of tumorigenicity by depleting exogenous gene components regarding iPSCs. It is generally assumed that clinical applications of human pluripotent stem cells should be limited to those cases where there are no alternative measures for treatments because of the risk in transplanting those cells to living bodies. Regarding lifestyle diseases, we have already several therapeutic options, and thus, development of human pluripotent stem cell-based therapeutics tends to be avoided. Nevertheless, human pluripotent stem cells can contribute to the development of new therapeutics in this field. As we will show, there is a case where only a short-term presence of human pluripotent stem-derived cells can exert long-term therapeutic effects even after they are rejected. In those cases, immunologically rejections of ESC- or allogenic iPSC-derived cells may produce beneficial outcomes by nullifying the risk of tumorigenesis without deterioration of therapeutic effects. Another utility of human pluripotent stem cells is the provision of an innovative tool for drug discovery that are otherwise unavailable. For example, clinical specimens of human classical brown adipocytes (BAs), which has been attracting a great deal of attention as a new target of drug discovery for the treatment of metabolic disorders, are unobtainable from living individuals due to scarcity, fragility and ethical problems. However, BA can easily be produced from human pluripotent stem cells. In this review, we will contemplate potential contribution of human pluripotent stem cells to therapeutic development for lifestyle diseases.

• Arteriostenosis
• Human embryonic stem cells
• Glucose intolerance
• Human induced pluripotent stem cells
• Brown adipose tissue

Free radical production and mitochondrial dysfunction during cardiac graft reperfusion is a major factor in post-transplant ischemia-reperfusion (IR) injury, an important underlying cause of primary graft dysfunction. We therefore assessed the efficacy of the mitochondria-targeted anti-oxidant MitoQ in reducing IR injury in a murine heterotopic cardiac transplant model.

Hearts from C57BL/6 donor mice were flushed with storage solution alone, solution containing the anti-oxidant MitoQ, or solution containing the non–anti-oxidant decyltriphenylphosphonium control and exposed to short (30 minutes) or prolonged (4 hour) cold preservation before transplantation. Grafts were transplanted into C57BL/6 recipients and analyzed for mitochondrial reactive oxygen species production, oxidative damage, serum troponin, beating score, and inflammatory markers 120 minutes or 24 hours post-transplant.

MitoQ was taken up by the heart during cold storage. Prolonged cold preservation of donor hearts before IR increased IR injury (troponin I, beating score) and mitochondrial reactive oxygen species, mitochondrial DNA damage, protein carbonyls, and pro-inflammatory cytokine release 24 hours after transplant. Administration of MitoQ to the donor heart in the storage solution protected against this IR injury by blocking graft oxidative damage and dampening the early pro-inflammatory response in the recipient.

IR after heart transplantation results in mitochondrial oxidative damage that is potentiated by cold ischemia. Supplementing donor graft perfusion with the anti-oxidant MitoQ before transplantation should be studied further to reduce IR-related free radical production, the innate immune response to IR injury, and subsequent donor cardiac injury.

• MitoQ
• ischemia
• mitochondria-targeted anti-oxidants
• reperfusion
• transplantation

• Animals
• Antioxidants/therapeutic use
• Disease Models, Animal
• Female
• Free Radical Scavengers/metabolism
• Heart Transplantation
• Male
• Mice
• Mice, Inbred C57BL
• Micronutrients/therapeutic use
• Mitochondria, Heart/metabolism
• Mitochondria, Heart/pathology
• Organ Preservation
• Organophosphorus Compounds/therapeutic use
• Oxidative Stress
• Primary Graft Dysfunction/etiology
• Primary Graft Dysfunction/metabolism
• Primary Graft Dysfunction/pathology
• Rats
• Rats, Wistar
• Reactive Oxygen Species
• Reperfusion Injury/etiology
• Reperfusion Injury/metabolism
• Reperfusion Injury/prevention & control
• Ubiquinone/analogs & derivatives
• Ubiquinone/therapeutic use

• MC_U105663142 Medical Research Council

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with donor lymphocyte infusion is the mainstay of treatment for many types of hematological malignancies, but the therapeutic effect and prevention of relapse is complicated by donor T-cell recognition and attack of host tissue in a process known as graft-versus-host disease (GvHD). Cytotoxic myeloablative conditioning regimens used prior to Allo-HSCT result in the release of endogenous innate immune activators that are increasingly recognized for their role in creating a pro-inflammatory milieu. This increased inflammatory state promotes allogeneic T-cell activation and the induction and perpetuation of GvHD. Here, we review the processes of cellular response to injury and cell death that are relevant following Allo-HSCT and present the current evidence for a causative role of a variety of endogenous innate immune activators in the mediation of sterile inflammation following Allo-HSCT. Finally, we discuss the potential therapeutic strategies that target the endogenous pathways of innate immune activation to decrease the incidence and severity of GvHD following Allo-HSCT.

• endogenous innate immune
• graft-versus-host disease
• hematopoietic stem cell transplantation
• tissue injury

• Animals
• Animals, Genetically Modified
• DNA, Mitochondrial/genetics
• Dogs
• Female
• Haplotypes
• Isografts/immunology
• Isografts/transplantation
• Nuclear Transfer Techniques
• Skin/immunology
• Skin Transplantation/methods

• Graft-versus-host disease
• Hematopoietic cell transplantation
• Mitochondria
• Polymorphism

• Hypoxia sensitivity
• Mouse C3H mtDNA
• Polymorphic mtDNA mutations
• Transmitochondrial cybrids
• Tumor phenotypes

• aging
• cancer
• dendritic cells
• immunopeptidome
• natural killer cells
• senescence

• mitochondrial metabolism
• oxidative phosphorylation
• oxphos
• inflammation
• tumor suppressor p53
• breast cancer

• Animals
• Breast Neoplasms/chemically induced
• Breast Neoplasms/metabolism
• Carcinogens, Environmental/toxicity
• Disease Susceptibility/chemically induced
• Disease Susceptibility/metabolism
• Environmental Exposure/adverse effects
• Female
• Humans
• Mammary Glands, Animal/drug effects
• Mammary Glands, Animal/metabolism
• Mammary Glands, Human/drug effects
• Mammary Glands, Human/metabolism
• Mitochondria/drug effects
• Mitochondria/metabolism
• Oxidative Phosphorylation/drug effects

• R21 NS057224 NINDS NIH HHS
• R21NS057224-01A2 NINDS NIH HHS

Human mesoangioblasts are currently in a phase I/II clinical trial for the treatment of patients with Duchenne muscular dystrophy. However, limitations associated with the finite life span of these cells combined with the significant numbers of mesoangioblasts required to treat all of the skeletal muscles in these patients restricts their therapeutic potential. Induced pluripotent stem cell (iPSC)-derived mesoangioblasts may provide the solution to this problem. Although, the idea of using iPSC-derived cell therapies has been proposed for quite some time, our understanding of how the immune system interacts with these cells is inadequate. Herein, we show that iPSC-derived mesoangioblasts (HIDEMs) from healthy donors and, importantly, limb-girdle muscular dystrophy 2D patients exert immunosuppressive effects on T cell proliferation.  Interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) play crucial roles in the initial activation of HIDEMs and importantly indoleamine 2,3 dioxygenase (IDO) and prostaglandin E2 (PGE-2) were identified as key mechanisms involved in HIDEM suppression of T cell proliferation. Together with recent studies confirming the myogenic function and regenerative potential of these cells, we suggest that HIDEMs could provide an unlimited alternative source for mesoangioblast-based therapies.

• Animals
• Apoptosis
• Autophagy
• Humans
• Mitochondria/genetics
• Mitochondria/metabolism
• Mitochondria/pathology
• Mitochondrial Diseases/pathology
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/pathology

• R01 GM062942 NIGMS NIH HHS
• R01 GM097432 NIGMS NIH HHS
• R01GM062942 NIGMS NIH HHS
• R01GM097432 NIGMS NIH HHS

The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.