Socialized mitochondria: mitonuclear crosstalk in stress.

Traditionally, mitochondria are considered sites of energy production. However, recent studies have suggested that mitochondria are signaling organelles that are involved in intracellular interactions with other organelles. Remarkably, stressed mitochondria appear to induce a beneficial response that restores mitochondrial function and cellular homeostasis. These mitochondrial stress-centered signaling pathways have been rapidly elucidated in multiple organisms. In this review, we examine current perspectives on how mitochondria communicate with the rest of the cell, highlighting mitochondria-to-nucleus (mitonuclear) communication under various stresses. Our understanding of mitochondria as signaling organelles may provide new insights into disease susceptibility and lifespan extension.

Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models.

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease.

Rationale: Mitochondrial dysfunction is a key factor in the pathogenesis of Parkinson's disease (PD). Accordingly, many aspects of mitochondrial function have been studied as a putative therapeutic target. Here we present a novel strategy to promote mitochondrial function and protect against Parkinson's disease by the peptide encoded within mitochondrial genome, mitochondria-derived peptide (MDP) humanin (HN). Methods: To test humanin as a potential biomarker in PD, we measured protein levels of circulating humanin from the plasma of PD patients and transgenic or neurotoxic mouse models of PD. Next, we aimed to identify whether HN peptide treatment can regulate its activity or expression. Using mouse models of PD, we assessed HN delivery to the brain via the nasal route of administration. We further revealed a possible mechanism underlying the therapeutic effectiveness of HN peptide for PD using in vitro and ex vivo model of PD. Results: Although the expression of intracellular HN was not correlated with PD, HN treatment itself could induce intracellular HN expression and enhance mitochondrial biogenesis inducing mitochondrial gene expression. After intranasal administration, HN peptide resulted in neuroprotection and behavioral recovery in an animal model of PD. Interestingly, HN peptide following intranasal delivery was found within the brain, mainly via the trigeminal pathways. Mechanistically, HN treatment induced activation of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway which led to enhanced mitochondrial biogenesis resulting in upregulation of mitochondrial gene including humanin. Conclusion: These data support a novel role of mitochondrial protein humanin in mitochondrial function and neuronal survival against Parkinson's disease, in which humanin treatment is sufficient for stimulating mitochondrial gene expression.

Adoptive therapy with amyloid-ß specific regulatory T cells alleviates Alzheimer's disease.

Rationale: Neuroinflammation is a primary feature of Alzheimer's disease (AD), for which an increasing number of drugs have been specifically developed. The present study aimed to define the therapeutic impact of a specific subpopulation of T cells that can suppress excessive inflammation in various immune and inflammatory disorders, namely, CD4+CD25+Foxp3+ regulatory T cells (Tregs). Methods: To generate Aß antigen-specific Tregs (Aß+ Tregs), Aß 1-42 peptide was applied in vivo and subsequent in vitro splenocyte culture. After isolating Tregs by magnetic bead based purification method, Aß+ Tregs were adoptively transferred into 3xTg-AD mice via tail vein injection. Therapeutic efficacy was confirmed with behavior test, Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining (IHC). In vitro suppression assay was performed to evaluate the suppressive activity of Aß+ Tregs using flow cytometry. Thy1.1+ Treg trafficking and distribution was analyzed to explore the infused Tregs migration into specific organs in an antigen-driven manner in AD mice. We further assessed cerebral glucose metabolism using 18F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of Aß+ Tregs toward Aß activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay. Results: We showed that Aß-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of Aß+ Tregs was enough to induce amelioration of cognitive impairments, Aß accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, Aß-specific Tregs effectively inhibited inflammation in primary microglia induced by Aß exposure. It may indicate bystander suppression in which Aß-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration. Conclusions: The administration of Aß antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.

Targeted Panel Sequencing Identifies an Intronic c.5225-3C>G Variant of the FBN1 Gene Causing Sporadic Marfan Syndrome with Annuloaortic Ectasia.

Marfan syndrome (MFS) is a hereditary connective tissue disease whose clinical severity varies widely. Mutations of the FBN1 gene encoding fibrillin-1 are the most common genetic cause of Marfanoid habitus; however, about 10% of MFS patients are unaware of their genetic defects. Herein, we report a Korean patient with MFS and annuloaortic ectasia caused by an intronic c.5225-3C>G variant of the FBN1 gene identified by targeted panel sequencing. The reverse transcription analysis of FBN1 revealed that the intron 43 sequence from positions c.5297-1516 to c.5297-1 was retained at the coding sequence as a consequence of the c.5225-3C>G variant enhancing a cryptic splice acceptor site (c.5297-1518_5297-1517AG) in intron 43. The retained sequence of the part of intron 43 caused the same effect as insertion mutation (NM_000138.5:c.5297_c.5298ins5297-1516_5297-1), resulting in a frameshift mutation resulting in p.Ile1767Trpfs*3. The patient underwent an urgent modified Bentall operation with a 29 mm mechanical valve for annuloaortic ectasia and severe aortic valve regurgitation. This report emphasizes the need for functional investigations into the diagnostic workflows of certain diseases or gene panels with suspected high rates of intronic variants and potential pathogenic effects. Hence, further descriptions of individuals with intronic variants causing alternative splicing expected to have pathogenic effects at different transcript levels are crucial for improving our understanding.

Particulate Matter Exacerbates the Death of Dopaminergic Neurons in Parkinson's Disease through an Inflammatory Response.

Particulate matter (PM), a component of air pollution, has been epidemiologically associated with a variety of diseases. Recent reports reveal that PM has detrimental effects on the brain. In this study, we aimed to investigate the biological effects of ambient particles on the neurodegenerative disease Parkinson's disease (PD). We exposed mice to coarse particles (PM10: 2.5-10 µm) for short (5 days) and long (8 weeks) durations via intratracheal instillation. Long-term PM10 exposure exacerbated motor impairment and dopaminergic neuron death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse models. Short-term PM10 exposure resulted in both pulmonary and systemic inflammatory responses in mice. We further investigated the mechanism underlying PM10-induced neurotoxicity in cocultures of lung LA-4 epithelial cells and RAW264.7 macrophages. PM10 treatment elicited a dramatic increase in proinflammatory mediators in LA-4/RAW264.7 coculture. Treating BV2 microglial cells with PM10-treated conditioned medium induced microglial activation. Furthermore, 1-methyl-4-phenylpyridinium (MPP+) treatment caused notable cell death in N2A neurons cocultured with activated BV2 cells in PM10-conditioned medium. Altogether, our results demonstrated that PM10 plays a role in the neurodegeneration associated with PD. Thus, the impact of PM10 on neurodegeneration could be related to detrimental air pollution-induced systemic effects on the brain.

Development of a Remote Displacement Measuring Laser System for Bridge Inspection.

Measuring displacement is essential for assessing the safety of bridges. Non-contact sensors such as vision sensors can precisely measure displacement but may be expensive or incapable of micro-scale measurement at a low cost, unlike contact displacement sensors, which are economical but challenging to install. This study proposes an economical, remote non-contact sensor system. The system comprises a laser beam transmitter and a light receiver, deriving the displacement based on the position where the laser beam is irradiated to the light-receiving surface. To measure this, the light receiver was installed at the measurement point and included a wireless communicator to transmit the displacement data. A displacement experiment was conducted to evaluate the performance. The results confirmed that precise displacement measurements were possible at a resolution of 100 µm. For bridge load tests, a light receiver under a bridge was installed, laser beams irradiated to the light-receiving surface from a distance, and the displacement was measured for each test and compared with the values measured by a conventional contact sensor. The results were highly consistent with those of the existing sensor, indicating that the proposed sensor system applies to bridge loading tests and the safety diagnosis for various structures.

Rapidly Growing Intra-Cardiac Mass Mimicking a Local Recurrence of Lung Cancer or a Thrombus in the Left Atrium.

Cardiac myxoma typically is thought to be a slow-growing, benign primary. Atrial myxomas can lead to many complications and can also mimic mitral stenosis, infective endocarditis, and other vascular diseases associated with systemic embolization. A 75-year-old woman with a history of lung cancer (pT1cN1, adenocarcinoma), atrial fibrillation, and a cerebral infarction presented with dysarthria and visual disturbances. In our case, we had to consider some questionable issues with the left atrial mass, and whether the recurrence of cerebral events was due to the thrombotic material in the left atrium or from locally recurrent lung cancer from the stump margin of the previously resected left superior pulmonary vein. We present a case with a rapidly-growing left atrial myxoma with a growth rate of 12.60 mm/month, rather than a thrombus or local recurrence of tumor under a medication of non-VKA oral antagonists.

Comparison of the Protective Effects of Bee Venom Extracts with Varying PLA2 Compositions in a Mouse Model of Parkinson's Disease.

Bee venom contains a number of pharmacologically active components, including enzymes and polypeptides such as phospholipase A2 (PLA2) and melittin, which have been shown to exhibit therapeutic benefits, mainly via attenuation of inflammation, neurotoxicity, and nociception. The individual components of bee venom may manifest distinct biological actions and therapeutic potential. In this study, the potential mechanisms of action of PLA2 and melittin, among different compounds purified from honey bee venom, were evaluated against Parkinson's disease (PD). Notably, bee venom PLA2 (bvPLA2), but not melittin, exhibited neuroprotective activity against PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MPTP-induced behavioral deficits were also abolished after bvPLA2 treatment, depending on the PLA2 content. Further, bvPLA2 administration activated regulatory T cells (Tregs) while inhibiting inflammatory T helper (Th) 1 and Th17 cells in the MPTP mouse model of PD. These results indicate that bvPLA2, but not melittin, protected against MPTP and alleviated inflammation in PD. Thus, bvPLA2 is a promising and effective therapeutic agent in Parkinson's disease.

Aortic Arch Endarterectomy Associated with On-Pump Cardiac Surgery in Patients with a Mobile Arch Atheroma.

We describe aortic arch endarterectomy performed concomitantly with on-pump cardiac surgery in 2 patients with grade V arch atherosclerosis. In both patients, transesophageal echocardiographic findings led to the diagnosis of severe arch atherosclerosis associated with a mobile atheromatous plaque in the aortic arch. The severe arch atherosclerosis was managed with endarterectomy under deep hypothermic circulatory arrest. In patients with severe grade V atherosclerosis in the aortic arch, performing endarterectomy simultaneously with primary cardiac surgery may be justified as a way to reduce the risk of peripheral embolism, including cerebrovascular accidents, with minimal additional surgical risk.

Dose-Dependent Neuroprotective Effect of Standardized Bee Venom Phospholipase A2 Against MPTP-Induced Parkinson's Disease in Mice.

Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by the selective loss of dopaminergic neurons within the substantia nigra (SN). While the precise etiology of dopaminergic neuronal demise is elusive, multiple lines of evidence indicate that neuroinflammation is involved in the pathogenesis of PD. We have previously demonstrated that subcutaneous administration of bee venom (BV) phospholipase A2 (bvPLA2) suppresses dopaminergic neuronal cell death in a PD mouse model. In the present study, we established standardized methods for producing bvPLA2 agent isolated from crude BV at good manufacturing practice (GMP) facility. The therapeutic efficacy of purified bvPLA2 agent was examined in MPTP-induced PD mice. Importantly, administration of purified bvPLA2 in a dose-dependent manner reversed motor deficits in PD mice as well as inhibited loss of dopaminergic neurons within the SN of PD mice. The concentration-dependent action of standardized bvPLA2 appeared to be related to the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs), which, in part, inhibits T helper 1 (Th1) and Th17 polarization and suppresses microglial activation in PD mice. Taken together, these results suggest that standardized bvPLA2 purified from BV shows a neuroprotective effect against PD and thus has a potential target for treatment of PD.

Dual inflow without circulatory arrest for hemiarch replacement.

BACKGROUND: Open distal graft to proximal aortic arch anastomosis is central to a hemiarch replacement. Even if the ischemic tolerance time of several organs during circulatory arrest (CA) at normothermia is much longer than that of the brain, very little is known about the safety and clinical efficacy of moderate hypothermia for organ protection during the average duration of CA needed for aortic arch replacement. Hemiarch replacement using the standard techniques of deep hypothermia and antegrade perfusion has often ignored the effects of prolonged distal body CA. Maintenance of distal organ, especially the liver and kidney, perfusion reduces the risk of postoperative renal dysfunction and coagulopathy. CASE PRESENTATION: A 72-year-old female patient was referred to our institute due to chest discomfort. Radiologic investigations revealed a giant aneurysm of the ascending aorta extending but confined to the proximal aortic arch. We performed an alternative technique for hemiarch replacement using a dual inflow source. CONCLUSIONS: Although this technique cannot apply to all aneurysmal aortic diseases, our basic technique involving the use of dual inflow may be well suited for standard hemiarch replacement that is confined to the proximal aortic arch, given the shortening of the bypass and ischemic times.

Rupture, Breakdown, and Pulmonary Artery Embolism of a Balloon Catheter Tip during Percutaneous Transluminal Angioplasty of Arteriovenous Fistula.

Percutaneous transluminal angioplasty is a well-known treatment for arteriovenous fistula stenosis. Balloon rupture during endovascular procedures is a rare but possible complication. The bursting balloon itself does not cause a serious problem, but it can occasionally cause entrapment, especially in case of breakdown of the balloon catheter tip. Here, we present four cases of balloon rupture during angioplasty in the hemodialysis circuit. In three cases, the ruptured balloon catheter was removed by cutdown of access conduit, while in one case, tip of ruptured balloon catheter was migrated into the pulmonary artery and was removed surgically. The operator must attempt to reduce the risk of balloon rupture by gradually expanding the balloons under bursting pressure. If the balloon bursts, it should not be removed excessively and attempt should be made to remove it using endovascular techniques. Surgical removal is considered after careful evaluation of the condition of the balloon and vessel.

Successful repair of coronary sinus rupture presenting as cardiac tamponade following blunt chest trauma.

The isolated coronary sinus (CS) rupture causing cardiac tamponade following blunt chest trauma is a very rare and very unique traumatic form of cardiac tamponade. Prompt recognition of this injury is crucial for patient survival. CS injuries are frequently difficult to repair and are potentially lethal. A meticulous repair carried out on an arrested, empty and well-protected heart is recommended to achieve secure haemostasis and CS patency. To our knowledge, this is the first report on the successful repair of isolated CS rupture following blunt chest trauma.

Aberrant right subclavian artery re-routing for hybrid repair of proximal descending aortic aneurysm.

BACKGROUND: An aberrant right subclavian artery (ARSA) is a relatively prevalent vascular anomaly. What is the most appropriate treatment for thoracic aortic aneurysm combined a non-aneurysmal change ARSA? CASE PRESENTATION: A 52-year-old man was admitted to our institute due to a history of chronic cough, dysphagia and an abnormal chest radiographic finding. Because of his progressive symptoms and large fusiform thoracic aneurysm, we performed the hybrid repair for simultaneous relief of an ARSA causing dysphagia and thoracic aneurysm. CONCLUSION: In case without aneurysm of ARSA, especially in conjunction with approximate thoracic aneurysm, our approach is suitable because the revascularization using the right carotid to subclavian artery re-routing prior to endograft deployment is justified in order to preserve circulation of posterior brain, spinal cord, internal mammary artery and upper limb and to prevent large retrograde type II endoleaks, as well as simplicity and durability.

Two-stage Surgical Treatment of a Giant Solitary Fibrous Tumor Occupying the Thoracic Cavity.

A solitary fibrous tumor (SFT) is a mesenchymal fibroblastic tumor inside the pleura, for which complete surgical resection is the standard treatment. For large SFTs, preoperative identification of tumor-feeding vessels using angiography is important for achieving complete resection without unexpected operative bleeding. Extensive adhesions can make resection difficult in a limited operative window, and pulmonary resection may be required to achieve complete SFT resection. Herein, we report successful resection of a large pleural SFT in a 39-year-old man without any complications using a 2-stage approach, in which ligation of the feeding vessels through small another operative window was the first step.

A standardized herbal extract PM014 ameliorates pulmonary fibrosis by suppressing the TGF-ß1 pathway.

Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease pathologically characterized by loss of epithelial cells and activation of fibroblasts and myofibroblasts. The etiology of IPF remains unclear and the disease pathology is poorly understood with no known efficacious therapy. PM014 is an herbal extract that has been shown to have beneficial effects in pulmonary diseases, which are likely to exert anti-inflammatory bioactions. In the present study, we observed that bleomycin (BLM) caused increased inflammatory infiltration as well as collagen deposition in lungs of mice on day 14 after treatment. Administration of PM014 suppressed BLM-induced inflammatory responses and fibrotic changes in dose-dependent manner in mice. Additionally, we provided in vitro evidence suggesting that PM014 inhibited TGF-ß1-induced epithelial-mesenchymal transition (EMT) and fibroblast activation in alveolar epithelial cells and human lung fibroblasts from healthy donor and IPF patients. PM014 appeared to target TGF-ß1 signaling via Smad-dependent pathways and p38 mitogen-activated protein kinases (MAPKs) pathways. Taken together, our data suggest that PM014 administration exerts a protective effect against lung fibrosis and highlight PM014 as a viable treatment option that may bring benefits to patient with IPF.

The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to Regulate Nuclear Gene Expression in Response to Metabolic Stress.

Cellular homeostasis is coordinated through communication between mitochondria and the nucleus, organelles that each possess their own genomes. Whereas the mitochondrial genome is regulated by factors encoded in the nucleus, the nuclear genome is currently not known to be actively controlled by factors encoded in the mitochondrial DNA. Here, we show that MOTS-c, a peptide encoded in the mitochondrial genome, translocates to the nucleus and regulates nuclear gene expression following metabolic stress in a 5'-adenosine monophosphate-activated protein kinase (AMPK)-dependent manner. In the nucleus, MOTS-c regulated a broad range of genes in response to glucose restriction, including those with antioxidant response elements (ARE), and interacted with ARE-regulating stress-responsive transcription factors, such as nuclear factor erythroid 2-related factor 2 (NFE2L2/NRF2). Our findings indicate that the mitochondrial and nuclear genomes co-evolved to independently encode for factors to cross-regulate each other, suggesting that mitonuclear communication is genetically integrated.