Mitochondrial disturbance related to increased caspase-1 of CD4+T cells in HIV-1 infection.

BACKGROUND: In HIV-1 infection, more than 95% of CD4+T cells die of caspase-1 mediated pyroptosis. What governs the increased susceptibility of CD4+T cells to pyroptosis is poorly understood. METHODS: Blood samples were obtained from 31 untreated HIV-infected patients (UNT), 29 antiretroviral therapy treated HIV-infected patients (ART), and 21 healthy control donors (HD). Plasma levels of IL-18 and IL-1ß, caspase-1 expression, mitochondrial mass (MM) and mitochondrial fusion/fisson genes of CD4+T subsets were measured. RESULTS: A significantly higher IL-18 level in plasma and MM level of CD4+T cells were found in HIV-infected patients (UNT and ART) compared to HD, and the MMhigh phenotype was manifested, related to increased caspase-1 expression. Moreover, the increased MM was more pronounced in the early differentiated and inactivated CD4+T cells. However, higher MM was not intrinsically linked to T cell differentiation disorder or excessive activation of the CD4+T cells. Mechanistically, the increased MM was significantly correlated with an elevated level of expression of the mitochondrial fusion gene mitofusin1. CONCLUSION: An increase in MM was associated with heightened sensitivity of CD4+T cells to pyroptosis, even in early differentiated and inactivated CD4+T cells, in patients with HIV-1 infection, regardless of whether patients were on antiretroviral therapy or not. These new revelations have uncovered a previously unappreciated challenge to immune reconstitution with antiretroviral therapy.

The immunoproteasome subunit ß2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Mitochondrial dynamics are critical for maintaining mitochondrial morphology and function during cardiac ischemia and reperfusion (I/R). The immunoproteasome complex is an inducible isoform of the proteasome that plays a key role in modulating inflammation and some cardiovascular diseases, but the importance of immunoproteasome catalytic subunit ß2i (also known as LMP10 or MECL1) in regulating mitochondrial dynamics and cardiac I/R injury is largely unknown. Here, using ß2i-knockout (KO) mice and rAAV9-ß2i-injected mice, we discovered that ß2i expression and its trypsin-like activity were significantly attenuated in the mouse I/R myocardium and in patients with myocardial infarction (MI). Moreover, ß2i-KO mice exhibited greatly enhanced I/R-mediated cardiac dysfunction, infarct size, myocyte apoptosis and oxidative stress accompanied by excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Conversely, cardiac overexpression of ß2i in mice injected with recombinant adeno-associated virus 9 (rAAV9)-ß2i ameliorated cardiac I/R injury. Mechanistically, I/R injury reduced ß2i expression and activity, which increased the expression of the E3 ligase Parkin protein and promoted the degradation of mitofusin 1/2 (Mfn1/2), leading to excessive mitochondrial fission. In conclusion, our data suggest for the first time that ß2i exerts a protective role against cardiac I/R injury and that increasing ß2i expression may be a new therapeutic option for cardiac ischemic disease in clinical practice. Graphical abstract showing how the immunoproteasome subunit ß2i ameliorates myocardial I/R injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

The Effect of Cold-Water Swimming on Energy Metabolism, Dynamics, and Mitochondrial Biogenesis in the Muscles of Aging Rats.

Our study aimed to explore the potential positive effects of cold water exercise on mitochondrial biogenesis and muscle energy metabolism in aging rats. The study involved 32 male and 32 female rats aged 15 months, randomly assigned to control sedentary animals, animals training in cold water at 5 ± 2 °C, or animals training in water at thermal comfort temperature (36 ± 2 °C). The rats underwent swimming training for nine weeks, gradually increasing the duration of the sessions from 2 min to 4 min per day, five days a week. The results demonstrated that swimming in thermally comfortable water improved the energy metabolism of aging rat muscles (increased metabolic rates expressed as increased ATP, ADP concentration, TAN (total adenine nucleotide) and AEC (adenylate energy charge value)) and increased mRNA and protein expression of fusion regulatory proteins. Similarly, cold-water swimming improved muscle energy metabolism in aging rats, as shown by an increase in muscle energy metabolites and enhanced mitochondrial biogenesis and dynamics. It can be concluded that the additive effect of daily activity in cold water influenced both an increase in the rate of energy metabolism in the muscles of the studied animals and an intensification of mitochondrial biogenesis and dynamics (related to fusion and fragmentation processes). Daily activity in warm water also resulted in an increase in the rate of energy metabolism in muscles, but at the same time did not cause significant changes in mitochondrial dynamics.

A detailed review of pharmacology of MFN1 (mitofusion-1)-mediated mitochondrial dynamics: Implications for cellular health and diseases.

The mitochondria are responsible for the production of cellular ATP, the regulation of cytosolic calcium levels, and the organization of numerous apoptotic proteins through the release of cofactors necessary for the activation of caspases. This level of functional adaptability can only be attained by sophisticated structural alignment. The morphology of the mitochondria does not remain unchanged throughout time; rather, it undergoes change as a result of processes known as fusion and fission. Fzo in flies, Fzo1 in yeast, and mitofusins in mammals are responsible for managing the outer mitochondrial membrane fusion process, whereas Mgm1 in yeast and optic atrophy 1 in mammals are responsible for managing the inner mitochondrial membrane fusion process. The fusion process is composed of two phases. MFN1, a GTPase that is located on the outer membrane of the mitochondria, is involved in the process of linking nearby mitochondria, maintaining the potential of the mitochondrial membrane, and apoptosis. This article offers specific information regarding the functions of MFN1 in a variety of cells and organs found in living creatures. According to the findings of the literature review, MFN1 plays an important part in a number of diseases and organ systems; nevertheless, the protein's function in other disease models and cell types has to be investigated in the near future so that it can be chosen as a promising marker for the therapeutic and diagnostic potentials it possesses. Overall, the major findings of this review highlight the pivotal role of mitofusin (MFN1) in regulating mitochondrial dynamics and its implications across various diseases, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndromes. Our review identifies novel therapeutic targets within the MFN1 signaling pathways and underscores the potential of MFN1 modulation as a promising strategy for treating mitochondrial-related diseases. Additionally, the review calls for further research into MFN1's molecular mechanisms to unlock new avenues for clinical interventions, emphasizing the need for targeted therapies that address MFN1 dysfunction.

Epidermal growth factor receptor promotes high-fructose nonalcoholic fatty liver disease by inducing mitochondrial fission in zebrafish.

Mitochondrial function has a pivotal role in the pathogenesis of NAFLD. Mitochondrial dynamics is a foundational activity underlying the maintenance of mitochondrial function in bioenergetics, the maintenance of MtDNA, calcium homeostasis, reactive oxygen species metabolism, and quality control. Loss of mitochondrial plasticity in terms of functions, morphology and dynamics may also be the critical switch from NAFLD/NASH to HCC. However, the cause of mitochondrial fission in NAFLD remains unclear. Recent studies have reported that EGFR can bind to Mfn1 and interfere with its polymerization. In this study, we investigated whether EGFR binds to Mfn1 in NAFLD, and whether reducing their binding can improve NAFLD in zebrafish model. Our results demonstrated that EGFR was activated in hepatocytes from high fructose (HF)-induced NAFLD zebrafish and interfered with Mfn1 polymerization, leading to reduction of MtDNA. Suppression of EGFR activation or mitochondrial translocation significantly improved mitochondrial morphology and increased mitochondrial DNA, ultimately preventing hepatic steatosis. In conclusion, these results suggest that EGFR binding to Mfn1 plays an important role in NAFLD zebrafish model and that inhibition of their binding could be a potential therapeutic target.

Increased mitochondrial fission induces NLRP3/cGAS-STING mediated pro-inflammatory pathways and apoptosis in UVB-irradiated immortalized human keratinocyte HaCaT cells.

Ultraviolet B (UVB) irradiation causes skin inflammation and apoptosis. Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Although dysfunction of mitochondria has been implicated in skin damages, little is known about the roles of mitochondrial dynamics in these processes. UVB irradiation increases abnormal mitochondrial content but decreases mitochondrial volume in immortalized human keratinocyte HaCaT cells. UVB irradiation resulted in marked upregulation of mitochondrial fission protein dynamin-related protein 1 (DRP1) and downregulation of mitochondrial outer membrane fusion proteins 1 and 2 (MFN1 and MFN2) in HaCaT cells. Mitochondrial dynamics was discovered to be crucial for NLRP3 inflammasome and cGAS-STING pathway activation, as well as the induction of apoptosis. Inhibition of mitochondrial fission by treatments with a DRP1 inhibitor, mdivi-1, or with DRP1-targeted siRNA, efficiently prevented UVB-induced NLRP3/cGAS-STING mediated pro-inflammatory pathways or apoptosis in the HaCaT cells, whereas inhibition of mitochondrial fusion with MFN1and 2 siRNA increased these pro-inflammatory pathways or apoptosis. The enhanced mitochondrial fission and reduced fusion caused the up-regulation of reactive oxygen species (ROS). Application of an antioxidant, N-acetyl-l-cysteine (NAC), which scavenges excessive ROS, attenuated inflammatory responses through suppressing NLRP3 inflammasome and cGAS-STING pathway activation, and rescued cells from apoptosis caused by UVB-irradiation. Together, our findings revealed the regulation of NLRP3/cGAS-STING inflammatory pathways and apoptosis by mitochondrial fission/fusion dynamics in UVB-irradiated HaCaT cells, providing a new strategy for the therapy of UVB skin injury.

PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.

BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulated by AMPK, is an important regulator of mitochondrial fusion. At present, whether the AMPK/PGC-1α signaling pathway regulates mitochondrial dynamics in epileptic rats is still unknown. METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into fourgroups: the control group (0.9% saline, n = 5), the EP groups (lithium-pilocarpine was used to induce epilepsy, and tissues were harvested at 6 and 24 h, every time point, n = 5), the EP + Compound C group (the specific inhibitor of PGC-1α, 15 mg/kg in 2% DMSO, n = 5), and the EP + DMSO group (0.9% saline + 2% DMSO, n = 5). To investigate whether PGC-1α participates in seizures by regulating the expression of mitofusin1/2(MFN1/2)in rats. RESULTS: In this study, the behavioral results indicate that the seizure susceptibility of the rats to epilepsy was increased when the expression of PGC-1α was inhibited. Subsequently, Western blot results suggested that the expression level of both MFN1 and MFN2 in the hippocampus was higher at 6 and 24 h after an epileptic seizure. Besides, the expression of PGC-1α and MFN2 was significantly decreased in the hippocampus when the epileptic rats were treated with Compound C. Furthermore, the immunofluorescence analysis of the localization of MFN1/2 and PGC-1α showed that MFN1/2 was mainly expressed in neurons but not astrocytes in the hippocampus and cerebral cortex of rats. Meanwhile, PGC-1α colocalized with the excitatory post-synaptic marker PSD95, suggesting that PGC-1α may regulate the seizure susceptibility of the rats by mediating excitatory post-synaptic signaling. CONCLUSION: The AMPK/PGC-1α signaling pathway may play an important role in the lithium-pilocarpine-induced epileptic rat model by mediating the expression of fusion proteins.

Mitochondrial fragmentation is crucial for c-Myc-driven hepatoblastoma-like liver tumors.

Hepatoblastoma is the most common liver cancer in children, and the aggressive subtype often has a poor prognosis and lacks effective targeted therapy. Although aggressive hepatoblastoma (HB) is often accompanied by abnormally high expression of the transcription factor c-Myc, the underlying mechanism remains unclear. In this study, we found that mitochondrial fragmentation was enhanced by c-Myc overexpression in human aggressive HB tissues and was associated with poor prognosis. Then, a mouse model resembling human HB was established via hydrodynamic injection of c-Myc plasmids. We observed that liver-specific knockout of the mitochondrial fusion molecule MFN1 or overexpression of mitochondrial fission molecule DRP1 promoted the occurrence of c-Myc-driven liver cancer. In contrast, when MFN1 was overexpressed in the liver, tumor formation was delayed. In vitro experiments showed that c-Myc transcriptionally upregulated the expression of DRP1 and decreased MFN1 expression through upregulation of miR-373-3p. Moreover, enhanced mitochondrial fragmentation significantly promoted aerobic glycolysis and the proliferation of HB cells by significantly increasing reactive oxygen species (ROS) production and activating the RAC-alpha serine/threonine-protein kinase (AKT)/mammalian target of rapamycin (mTOR) and nuclear factor κB (NF-κB) pathways. Taken together, our results indicate that c-Myc-mediated mitochondrial fragmentation promotes the malignant transformation and progression of HB by activating ROS-mediated multi-oncogenic signaling.

Mitofusin 2 but not mitofusin 1 mediates Bcl-XL-induced mitochondrial aggregation.

Bcl-2 family proteins, as central players of the apoptotic program, participate in regulation of the mitochondrial network. Here, a quantitative live-cell fluorescence resonance energy transfer (FRET) two-hybrid assay was used to confirm the homo-/hetero-oligomerization of mitofusins 2 and 1 (MFN2 and MFN1), and also demonstrate the binding of MFN2 to MFN1 with 1:1 stoichiometry. A FRET two-hybrid assay for living cells co-expressing CFP-labeled Bcl-XL (an anti-apoptotic Bcl-2 family protein encoded by BCL2L1) and YFP-labeled MFN2 or MFN1 demonstrated the binding of MFN2 or MFN1 to Bcl-XL with 1:1 stoichiometry. Neither MFN2 nor MFN1 bound with monomeric Bax in healthy cells, but both MFN2 and MFN1 bind to punctate Bax (pro-apoptotic Bcl-2 family protein) during apoptosis. Oligomerized Bak (also known as BAK1; a pro-apoptotic Bcl-2 family protein) only associated with MFN1 but not MFN2. Moreover, co-expression of Bcl-XL with MFN2 or MFN1 had the same anti-apoptotic effect as the expression of Bcl-XL alone to staurosporine-induced apoptosis, indicating the Bcl-XL has its full anti-apoptotic ability when complexed with MFN2 or MFN1. However, knockdown of MFN2 but not MFN1 reduced mitochondrial aggregation induced by overexpression of Bcl-XL, indicating that MFN2 but not MFN1 mediates Bcl-XL-induced mitochondrial aggregation.

Selenium Alleviates Cerebral Ischemia/Reperfusion Injury by Regulating Oxidative Stress, Mitochondrial Fusion and Ferroptosis.

To clarify the potential role of selenium (Se) on cerebral ischemia/reperfusion (I/R) injury, we utilized mouse middle cerebral artery occlusion (MCAO) followed by reperfusion as an animal model and oxygen-glucose deprivation and reoxygenation (OGD/R) to treat N2a cells as a cell model, respectively. MCAO model was established in mice and then divided into different groups with or without Se treatment. TTC staining was used to observe whether the cerebral I/R modeling was successful, and the apoptosis level was determined by TUNEL staining. The expression of GPx-4 and p22phox was assessed by western blot. In vitro experiments, the OGD/R induced oxidative stress in N2a cells was assessed by levels of GSH/GSSG, malondialdehyde, superoxide dismutase and iron content, respectively. QRT-PCR was used to detect the mRNA levels of Cox-2, Fth1, Mfn1 and mtDNA in N2a cells. JC-1 staining and flow cytometry was performed to detect the mitochondrial membrane potential. Se treatment alleviated cerebral I/R injury and improved the survival rate of mice. Additionally, Se treatment apparently attenuated oxidative stress and inhibited iron accumulation in MCAO model mice and OGD/R model of N2a cells. In terms of its mechanism, Se could up-regulate Mfn1 expression to alleviate oxidative stress and ferroptosis by promoting mitochondrial fusion in vivo and vitro. These findings suggest that Se may have great potential in alleviating cerebral I/R injury.

MIEF1/2 orchestrate mitochondrial dynamics through direct engagement with both the fission and fusion machineries.

BACKGROUND: Mitochondrial dynamics is the result of a dynamic balance between fusion and fission events, which are driven via a set of mitochondria-shaping proteins. These proteins are generally considered to be binary components of either the fission or fusion machinery, but potential crosstalk between the fission and fusion machineries remains less explored. In the present work, we analyzed the roles of mitochondrial elongation factors 1 and 2 (MIEF1/2), core components of the fission machinery in mammals. RESULTS: We show that MIEFs (MIEF1/2), besides their action in the fission machinery, regulate mitochondrial fusion through direct interaction with the fusion proteins Mfn1 and Mfn2, suggesting that MIEFs participate in not only fission but also fusion. Elevated levels of MIEFs enhance mitochondrial fusion in an Mfn1/2- and OPA1-dependent but Drp1-independent manner. Moreover, mitochondrial localization and self-association of MIEFs are crucial for their fusion-promoting ability. In addition, we show that MIEF1/2 can competitively decrease the interaction of hFis1 with Mfn1 and Mfn2, alleviating hFis1-induced mitochondrial fragmentation and contributing to mitochondrial fusion. CONCLUSIONS: Our study suggests that MIEFs serve as a central hub that interacts with and regulates both the fission and fusion machineries, which uncovers a novel mechanism for balancing these opposing forces of mitochondrial dynamics in mammals.

Mitochondrial Fusion Mediated by Mitofusin 1 Regulates Macrophage Mycobactericidal Activity by Enhancing Autophagy.

A mitochondrion, as a highly dynamic organelle, continuously changes morphology and position during its life cycle. Mitochondrial dynamics, including fission and fusion, play a critical role in maintaining functional mitochondria for ATP production, which is directly linked to host defense against Mycobacterium tuberculosis infection. However, how macrophages regulate mitochondrial dynamics during M. tuberculosis infection remains elusive. In this study, we found that M. tuberculosis infection induced mitochondrial fusion by enhancing the expression of mitofusin 1 (MFN1), which resulted in increased ATP production. Silencing of MFN1 inhibited mitochondrial fusion and subsequently reduced ATP production, which, in turn, severely impaired macrophages' mycobactericidal activity by inhibiting autophagy. Impairment of mycobactericidal activity and autophagy was replicated using oligomycin, an inhibitor of ATP synthase. In summary, our study revealed that MFN1-mediated mitochondrial fusion is essential for macrophages' mycobactericidal activity through the regulation of ATP-dependent autophagy. The MFN1-mediated metabolism pathway might be a target for the development of a host direct therapy (HDT) strategy against tuberculosis.

Mitofusin 1 is required for oocyte growth and communication with follicular somatic cells.

Mitochondrial function, largely regulated by the dynamics of this organelle, is inextricably linked to the oocyte health. In comparison with most somatic cells, mitochondria in oocytes are smaller and rounder in appearance, suggesting limited fusion. The functional implications of this distinct morphology, and how changes in the mitochondrial shape translate to mitochondrial function in oogenesis is little understood. We, therefore, asked whether the pro-fusion proteins mitofusins 1 (MFN1) and 2 (MFN2) are required for the oocyte development. Here we show that oocyte-specific deletion of Mfn1, but not Mfn2, prevents the oocyte growth and ovulation due to a block in folliculogenesis. We pinpoint the loss of oocyte growth and ovulation to impaired PI3K-Akt signaling and disrupted oocyte-somatic cell communication. In support, the double loss of Mfn1 and Mfn2 partially rescues the impaired PI3K-Akt signaling and defects in oocyte development secondary to the single loss of Mfn1. Together, this work demonstrates that the mitochondrial function influences the cellular signaling during the oocyte development, and highlights the importance of distinct, nonredundant roles of MFN1 and MFN2 in oogenesis.

MFN1 and MFN2 Are Dispensable for Sperm Development and Functions in Mice.

MFN1 (Mitofusin 1) and MFN2 (Mitofusin 2) are GTPases essential for mitochondrial fusion. Published studies revealed crucial roles of both Mitofusins during embryonic development. Despite the unique mitochondrial organization in sperm flagella, the biological requirement in sperm development and functions remain undefined. Here, using sperm-specific Cre drivers, we show that either Mfn1 or Mfn2 knockout in haploid germ cells does not affect male fertility. The Mfn1 and Mfn2 double knockout mice were further analyzed. We found no differences in testis morphology and weight between Mfn-deficient mice and their wild-type littermate controls. Spermatogenesis was normal in Mfn double knockout mice, in which properly developed TRA98+ germ cells, SYCP3+ spermatocytes, and TNP1+ spermatids/spermatozoa were detected in seminiferous tubules, indicating that sperm formation was not disrupted upon MFN deficiency. Collectively, our findings reveal that both MFN1 and MFN2 are dispensable for sperm development and functions in mice.

Notch1 protects against myocardial ischaemia-reperfusion injury via regulating mitochondrial fusion and function.

Mitochondrial fusion and fission dynamic are critical to the myocardial protection against ischaemia-reperfusion injury. Notch1 signalling plays an important role in heart development, maturation and repair. However, the role of Notch1 in the myocardial mitochondrial fusion and fission dynamic remains elusive. Here, we isolated myocardial cells from rats and established myocardial ischaemia-reperfusion injury (IRI) model. We modulated Notch1, MFN1 and DRP1 expression levels in myocardial cells via infection with recombinant adenoviruses. The results showed that Notch1 improves the cell viability and mitochondrial fusion in myocardiocytes exposed to IRI. These improvements were dependent on the regulation of MFN1 and DRP1. On the mechanism, we found that MNF1 is transcriptionally activated by RBP-Jk in myocardiocytes. Notch1 also improves the mitochondrial membrane potential in myocardiocytes exposed to IRI. Moreover, we further confirmed the protection of the Notch1-MFN1/Drp1 axis on the post-ischaemic recovery of myocardial performance is associated with the preservation of the mitochondrial structure. In conclusion, this study presented a detailed mechanism by which Notch1 signalling improves mitochondrial fusion during myocardial protection.

Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.

AIM: Muscle weakness is commonly among chronic kidney disease (CKD) patients. Muscle mitochondrial dysfunction and decreased pyruvate dehydrogenase (PDH) activity occur in CKD animals but have not been confirmed in humans, and changes in pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP) expression have not been evaluated in CKD muscle. We presume that the reduction of muscle mitochondria and post-translational modification of PDH may cause muscle weakness in CKD patients. Herein, we explored changes in mitochondrial morphology, PDH expression and activity, and PDK/PDP expression in CKD patient muscle. METHODS: Twenty patients with stage 4-5 CKD (CKD group) and 24 volunteers (control group) were included. Clinical characteristics, biochemical information and handgrip strength (HGS) were determined. Skeletal muscle samples were collected from eight stage 5 CKD patients from CKD group. Other eight non-CKD surgical subjects' muscle samples were collected as control. PDH activity was determined using a PDH enzyme activity assay kit, and real-time PCR and western blotting analyses were performed to measure gene expression and protein levels, respectively. Transmission electron microscopy was used to study mitochondria morphology. RESULTS: CKD patients had lower HGS than non-CKD subjects, and HGS was correlated with gender, age, haemoglobin and albumin. Mitochondria were decreased in end-stage renal disease (ESRD) patients muscle. Mfn-1 expression and phospho-Drp1(S637)/Drp1 ratio were inhibited in the ESRD group, implicating dysfunctional mitochondrial dynamics. Muscle PDH activity and phospho-PDH(S293) were decreased in ESRD patient muscle, while PDK4 protein level was up regulated. CONCLUSION: Decreased mitochondria and PDH deficiency caused by up regulation of PDK 4 contribute to muscle dysfunction, and could be responsible for muscle weakness in CKD patients.

Mito-Morphosis: Mitochondrial Fusion, Fission, and Cristae Remodeling as Key Mediators of Cellular Function.

Permanent residency in the eukaryotic cell pressured the prokaryotic mitochondrial ancestor to strategize for intracellular living. Mitochondria are able to autonomously integrate and respond to cellular cues and demands by remodeling their morphology. These processes define mitochondrial dynamics and inextricably link the fate of the mitochondrion and that of the host eukaryote, as exemplified by the human diseases that result from mutations in mitochondrial dynamics proteins. In this review, we delineate the architecture of mitochondria and define the mechanisms by which they modify their shape. Key players in these mechanisms are discussed, along with their role in manipulating mitochondrial morphology during cellular action and development. Throughout, we highlight the evolutionary context in which mitochondrial dynamics emerged and consider unanswered questions whose dissection might lead to mitochondrial morphology-based therapies.

Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion.

Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration.

Mitochondrial Dynamics in Tachycardiomyopathy.

BACKGROUND/AIMS: Tachycardiomyopathy (TCM) is a largely reversible form of non-ischemic heart failure. The underlying mechanism are, however, still today poorly understood. Recent data indicate distinct changes in mitochondrial distribution in these patients, compared to other non-ischemic cardiomyopathies.This study investigated underlying mechanisms in mitochondrial dynamics in endomyocardial biopsy samples (EMB) from patients with TCM and compared them to patients with dilated cardiomyopathy (DCM), which show similar clinical features. METHODS: Focused mRNA analyses were performed on routinely obtained paraffinfixed EMB specimen from patients fulfilling TCM diagnosis criteria, as well as patients with DCM to elucidate regulatory changes in mitochondrial fusion, fission and mitophagy. RESULTS: In patients with TCM we were able to identify mRNA of Mitofusin 1 and 2, two effector proteins regulating mitochondrial fusion, to be strongly upregulated compared to patients with DCM. Conclusively, we did not find differences in the mRNA expression of mitochondrial fission regulators including DRP1, Fis1, MFF, MiD49, and MiD51. Furthermore, we did not find significant changes in PINK1 expression, an important mediator for mitochondrial autophagy. CONCLUSION: The mRNA upregulation of Mitofusin 1 and 2 provides first insight into the complex changes of mitochondrial dynamics in cardiomyocytes of patients with reversible heart failure due to TCM.

Protective effect of agmatine against hyperoxia-induced acute lung injury via regulating lncRNA gadd7.

Hyperoxia-induced acute lung injury (HALI) is a kind of iatrogenic pulmonary dysfunction caused by the prolonged exposure to high concentrations of oxygen, which is commonly seen in the treatment of refractory hypoxemia. Agmatine (AGM), a biogenic amine metabolite of l-arginine, induces a variety of physiological and pharmacological effects in the body. In this study, we investigated the protective effect of AGM on hyperoxia-induced lung injury and explored the underlying mechanism. A series of methods were used including flow cytometry, tunnel assay, dual-luciferase reporter assay, qRT-PCR and Western blotting. The results indicate that AGM can protect hyperoxia-induced lung injury. Further studies suggest that AGM decreased the upregulated expression of lncRNA gadd7 caused by hyperoxia and due to the presence of the competitive binding of lncRNA gadd7 and MFN1 to miR-125a, AGM indirectly decreased MFN1 protein expression to inhibit the cells apoptosis. In conclusion, AGM protects hyperoxia-induced lung injury by decreasing the expression of lncRNA gadd7 to regulate MFN1 expression.