scholarly journals Repeated hypoglycemia blunts the responsiveness of glucose-inhibited GHRH neurons by remodeling neural inputs and disrupting mitochondrial structure and function

2019 ◽  
Author(s):  
M Bayne ◽  
A Alvarsson ◽  
K Devarakonda ◽  
R Li ◽  
M Jimenez-Gonzalez ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Glucose Deprivation ◽  
Glucose Sensing ◽  
Diabetic Patients ◽  
Hypoglycemia Unawareness ◽  
Atp Production ◽  
Low Glucose

AbstractHypoglycemia is a frequent complication of diabetes, limiting therapy and increasing morbidity and mortality. With recurrent hypoglycemia, the counter-regulatory response (CRR) to decreased blood glucose is blunted, resulting in hypoglycemia unawareness. The mechanisms leading to these blunted effects remain incompletely understood. Here, we identify, with in situ hybridization, immunohistochemistry and the tissue clearing capability of iDisco, that GHRH neurons represent a unique population of arcuate nucleus neurons activated by glucose deprivation in vivo. Repeated glucose deprivation reduces GHRH neuron activation and remodels excitatory and inhibitory inputs to GHRH neurons. We show low glucose sensing is coupled to GHRH neuron depolarization, decreased ATP production and mitochondrial fusion. Repeated hypoglycemia attenuates these responses during low glucose. By maintaining mitochondrial length with the small molecule, mdivi-1, we preserved hypoglycemia sensitivity in vitro and in vivo. Our findings present possible mechanisms for the blunting of the CRR, broaden significantly our understanding of the structure of GHRH neurons and for the fist time, propose that mitochondrial dynamics play an important role in hypoglycemia unawareness. We conclude that interventions targeting mitochondrial fission in GHRH neurons may offer a new pathway to prevent hypoglycemia unawareness in diabetic patients.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

scholarly journals NIK promotes metabolic adaptation of glioblastoma cells to bioenergetic stress

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Michael L. Kamradt ◽  
Ji-Ung Jung ◽  
Kathryn M. Pflug ◽  
Dong W. Lee ◽  
Victor Fanniel ◽  
...  
Keyword(s):  
Stress Responses ◽  
Glucose Deprivation ◽  
Metabolic Adaptation ◽  
Mitochondrial Morphology ◽  
Atp Production ◽  
Tumor Microenvironments ◽  
Iκb Kinase ◽  
Critical Measure

AbstractCancers, including glioblastoma multiforme (GBM), undergo coordinated reprogramming of metabolic pathways that control glycolysis and oxidative phosphorylation (OXPHOS) to promote tumor growth in diverse tumor microenvironments. Adaptation to limited nutrient availability in the microenvironment is associated with remodeling of mitochondrial morphology and bioenergetic capacity. We recently demonstrated that NF-κB-inducing kinase (NIK) regulates mitochondrial morphology to promote GBM cell invasion. Here, we show that NIK is recruited to the outer membrane of dividing mitochondria with the master fission regulator, Dynamin-related protein1 (DRP1). Moreover, glucose deprivation-mediated metabolic shift to OXPHOS increases fission and mitochondrial localization of both NIK and DRP1. NIK deficiency results in decreased mitochondrial respiration, ATP production, and spare respiratory capacity (SRC), a critical measure of mitochondrial fitness. Although IκB kinase α and β (IKKα/β) and NIK are required for OXPHOS in high glucose media, only NIK is required to increase SRC under glucose deprivation. Consistent with an IKK-independent role for NIK in regulating metabolism, we show that NIK phosphorylates DRP1-S616 in vitro and in vivo. Notably, a constitutively active DRP1-S616E mutant rescues oxidative metabolism, invasiveness, and tumorigenic potential in NIK−/− cells without inducing IKK. Thus, we establish that NIK is critical for bioenergetic stress responses to promote GBM cell pathogenesis independently of IKK. Our data suggest that targeting NIK may be used to exploit metabolic vulnerabilities and improve therapeutic strategies for GBM.

scholarly journals PIM Kinases Alter Mitochondrial Dynamics and Chemosensitivity in Lung Cancer

2019 ◽  
Author(s):  
Shailender S. Chauhan ◽  
Rachel K. Toth ◽  
Corbin C. Jensen ◽  
Andrea L. Casillas ◽  
David F. Kashatus ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mitochondrial Dynamics ◽  
Nsclc Patient ◽  
Mitochondrial Fission ◽  
Inverse Correlation ◽  
Mitochondrial Superoxide ◽  
Pim Kinases ◽  
Response To Chemotherapy

AbstractResistance to chemotherapy represents a major obstacle to the successful treatment of non-small cell lung cancer (NSCLC). The goal of this study was to determine how PIM kinases impact mitochondrial dynamics, ROS production, and response to chemotherapy in lung cancer. Live cell imaging and microscopy were used to determine the effect of PIM loss or inhibition on mitochondrial phenotype and ROS. Inhibition of PIM kinases caused excessive mitochondrial fission and significant upregulation of mitochondrial superoxide, increasing intercellular ROS. Mechanistically, we define a signaling axis linking PIM1 to Drp1 and mitochondrial fission in lung cancer. PIM inhibition significantly increased the protein levels and mitochondrial localization of Drp1, causing marked fragmentation of mitochondria. An inverse correlation between PIM1 and Drp1 was confirmed in NSCLC patient samples. Inhibition of PIM sensitized NSCLC to chemotherapy and produced a synergistic anti-tumor response in vitro and in vivo. Immunohistochemistry and transmission electron microscopy verified that PIM inhibitors promote mitochondrial fission and apoptosis in vivo. These data improve our knowledge about how PIM1 regulates mitochondria and provide justification for combining PIM inhibition with chemotherapy in NSCLC.

scholarly journals SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics to induce robust virus propagation

2021 ◽  
Author(s):  
Hye Jin Shin ◽  
Keun Bon Ku ◽  
Gun Young Yoon ◽  
Hyun-Woo Moon ◽  
Chonsaeng Kim ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Egfr Inhibitors ◽  
Respiratory Pathogen ◽  
Aged Mouse ◽  
Mitochondrial Bioenergetics ◽  
Virus Propagation ◽  
Atp Production ◽  
Signal Cascade

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a respiratory pathogen leading to serious multi-organ damage. However, little is known about SARS-CoV-2-induced cellular alterations for understanding robust virus propagation yet. Here we report that SARS-CoV-2 aberrantly elevates mitochondrial bioenergetics and activates epidermal growth factor receptor (EGFR)-mediated cell survival signal cascade for sustaining persistence of SARS-CoV-2. We found that SARS-CoV-2 causes increase in mitochondrial transmembrane potential by SARS-CoV-2 RNA-nucleocapsid cluster, thereby abnormally promoting mitochondrial biogenesis and oxidative phosphorylation (OXPHOS) process followed by abundant ATP production. SARS-CoV-2 also activated EGFR signal cascade and subsequent mitochondrial EGFR accumulation which contributes to the maintenance of abnormal OXPHOS and viral propagation. Therapeutic options for the treatment of COVID-19 are still inadequate. The FDA-approved EGFR inhibitors caused a remarkable reduction in SARS-CoV-2 propagation. Among EGFR inhibitors, vandetanib showing the highest anti-SARS-CoV-2 efficacy exhibited the potent antiviral activity against various SARS-CoV-2 variants including B.1.1.7 (UK variant) and B.1.351 (SA variant) lineages in both in vitro cell culture and in vivo animal experiments using wild-type aged mouse susceptible to SARS-CoV-2 infection, suggesting that EGFR is an attractive host target for combatting COVID-19. Overall, our results suggest that SARS-CoV-2 induces aberrant mitochondrial dynamics and bioenergetics, which significantly contributes to robust SARS-CoV-2 propagation.

scholarly journals Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

2015 ◽  
Vol 35 (5) ◽  
pp. 851-860 ◽  
Author(s):  
Alberto Julio-Amilpas ◽  
Teresa Montiel ◽  
Eva Soto-Tinoco ◽  
Cristian Gerónimo-Olvera ◽  
Lourdes Massieu
Keyword(s):  
Reactive Oxygen Species ◽  
Protective Effect ◽  
Neuronal Death ◽  
Ketone Bodies ◽  
Reactive Oxygen ◽  
Glucose Deprivation ◽  
Oxygen Species ◽  
Atp Production

Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury.

scholarly journals Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage

2016 ◽  
Vol 37 (2) ◽  
pp. 514-527 ◽  
Author(s):  
Naomi L Sayre ◽  
Mikaela Sifuentes ◽  
Deborah Holstein ◽  
Sheue-yann Cheng ◽  
Xuguang Zhu ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Fatty Acid ◽  
Stroke Volume ◽  
Fatty Acid Oxidation ◽  
Glucose Deprivation ◽  
Acid Oxidation ◽  
Atp Production ◽  
Stimulation Of

We previously demonstrated that stimulation of astrocyte mitochondrial ATP production via P2Y1 receptor agonists was neuroprotective after cerebral ischemic stroke. Another mechanism that increases ATP production is fatty acid oxidation (FAO). We show that in primary human astrocytes, FAO and ATP production are stimulated by 3,3,5 triiodo-l-thyronine (T3). We tested whether T3-stimulated FAO enhances neuroprotection, and show that T3 increased astrocyte survival after either hydrogen peroxide exposure or oxygen glucose deprivation. T3-mediated ATP production and protection were both eliminated with etomoxir, an inhibitor of FAO. T3-mediated protection in vitro was also dependent on astrocytes expressing HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase), which we previously showed was critical for T3-mediated FAO in fibroblasts. Consistent with previous reports, T3-treatment decreased stroke volumes in mice. While T3 decreased stroke volume in etomoxir-treated mice, T3 had no protective effect on stroke volume in HADHA +/− mice or in mice unable to upregulate astrocyte-specific energy production. In vivo, 95% of HADHA co-localize with glial-fibrillary acidic protein, suggesting the effect of HADHA is astrocyte mediated. These results suggest that astrocyte-FAO modulates lesion size and is required for T3-mediated neuroprotection post-stroke. To our knowledge, this is the first report of a neuroprotective role for FAO in the brain.

scholarly journals Mitochondrial Dynamics Markers and Related Signaling Molecules Are Important Regulators of Spermatozoa Number and Functionality

2021 ◽  
Vol 22 (11) ◽  
pp. 5693
Author(s):  
Isidora M. Starovlah ◽  
Sava M. Radovic Pletikosic ◽  
Tatjana S. Kostic ◽  
Silvana A. Andric
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mapk Signaling ◽  
Signaling Molecules ◽  
Transcriptional Profile ◽  
Human Society ◽  
Adult Rats ◽  
Atp Production ◽  
Adaptive Mechanisms

Here, we study possible mechanisms of (in/sub)fertility related to the acute or repeated psychological stresses (the most common stresses in human society) by following the transcriptional profile of 22 mitochondrial dynamics/function markers and 22 signaling molecules regulating both mitochondrial dynamics and spermatozoa number/functionality. An in vivo study mimicking acute (once for 3 h) and repeated (3 h for 10 consecutive days) psychophysical stress was performed on adult rats. The analysis of hormones, the number/functionality of spermatozoa, and 44 transcriptional markers were performed on individual samples from up to 12 animals per group. Results showed that both types of stress reduced spermatozoa functionality (acute by 4.4-fold, repeated by 3.3-fold) and ATP production (acute by 2.3-fold, repeated by 14.5-fold), while only repeated stress reduces the number of spermatozoa (1.9-fold). Stress significantly disturbed transcription of 34-out-of-44 markers (77%). Mitochondrial dynamics and functionality markers: 18-out-of-22 =>82% (mitochondrial-biogenesis-markers –>6-out-of-8 =>75%; mitochondrial-fusion-markers –>3-out-of-3 =>100%; mitochondrial-fission-markers –>1-out-of-2 =>50%; mitochondrial-autophagy-markers –>3-out-of-3 =>100%; mitochondrial-functionality-markers –>5-out-of-6 =>83%). Markers of signaling pathways regulating both mitochondrial dynamics/functionality and spermatozoa number/functionality important for male (in/sub)fertility –>16-out-of-22 =>73% (cAMP-signaling-markers –>8-out-of-12 =>67%; MAPK-signaling-markers –>8-out-of-10 =>80%). Accordingly, stress-triggered changes of transcriptional profile of mitochondrial dynamics/functionality markers as well as signaling molecules regulating both mitochondrial dynamics and spermatozoa number and functionality represent adaptive mechanisms.

scholarly journals SENP3 Promotes an Mff-Primed Bcl-xL-Drp1 Interaction Involved in Cell Death Following Ischemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Chun Guo ◽  
Keri L. Hildick ◽  
Juwei Jiang ◽  
Alice Zhao ◽  
Wenbin Guo ◽  
...  
Keyword(s):  
Cell Death ◽  
Mitochondrial Fission ◽  
Glucose Deprivation ◽  
Mitochondrial Outer Membrane ◽  
Sumo Protease ◽  
Survival Pathways ◽  
Sumo Target ◽  
In Cells

Dysregulation of the mitochondrial fission machinery has been linked to cell death following ischemia. Fission is largely dependent on recruitment of Dynamin-related protein 1 (Drp1) to the receptor Mitochondrial fission factor (Mff) located on the mitochondrial outer membrane (MOM). Drp1 is a target for SUMOylation and its deSUMOylation, mediated by the SUMO protease SENP3, enhances the Drp1-Mff interaction to promote cell death in an oxygen/glucose deprivation (OGD) model of ischemia. Another interacting partner for Drp1 is the Bcl-2 family member Bcl-xL, an important protein in cell death and survival pathways. Here we demonstrate that preventing Drp1 SUMOylation by mutating its SUMO target lysines enhances the Drp1-Bcl-xL interaction in vivo and in vitro. Moreover, SENP3-mediated deSUMOylation of Drp1 promotes the Drp1-Bcl-xL interaction. Our data suggest that Mff primes Drp1 binding to Bcl-xL at the mitochondria and that Mff and Bcl-xL can interact directly, independent of Drp1, through their transmembrane domains. Importantly, SENP3 loss in cells subjected to OGD correlates with reduced Drp1-Bcl-xL interaction, whilst recovery of SENP3 levels in cells subjected to reoxygenation following OGD correlates with increased Drp1-Bcl-xL interaction. Expressing a Bcl-xL mutant with defective Drp1 binding reduces OGD plus reoxygenation-evoked cell death. Taken together, our results indicate that SENP3-mediated deSUMOlyation promotes an Mff-primed Drp1-Bcl-xL interaction that contributes to cell death following ischemia.

scholarly journals A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009129
Author(s):  
Daniel C. Maddison ◽  
Mónica Alfonso-Núñez ◽  
Aisha M. Swaih ◽  
Carlo Breda ◽  
Susanna Campesan ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Translational Regulation ◽  
Metabolic Flux ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Kynurenine Pathway ◽  
Loss Of Function ◽  
Disease Associated Genes

The enzyme kynurenine 3-monooxygenase (KMO) operates at a critical branch-point in the kynurenine pathway (KP), the major route of tryptophan metabolism. As the KP has been implicated in the pathogenesis of several human diseases, KMO and other enzymes that control metabolic flux through the pathway are potential therapeutic targets for these disorders. While KMO is localized to the outer mitochondrial membrane in eukaryotic organisms, no mitochondrial role for KMO has been described. In this study, KMO deficient Drosophila melanogaster were investigated for mitochondrial phenotypes in vitro and in vivo. We find that a loss of function allele or RNAi knockdown of the Drosophila KMO ortholog (cinnabar) causes a range of morphological and functional alterations to mitochondria, which are independent of changes to levels of KP metabolites. Notably, cinnabar genetically interacts with the Parkinson’s disease associated genes Pink1 and parkin, as well as the mitochondrial fission gene Drp1, implicating KMO in mitochondrial dynamics and mitophagy, mechanisms which govern the maintenance of a healthy mitochondrial network. Overexpression of human KMO in mammalian cells finds that KMO plays a role in the post-translational regulation of DRP1. These findings reveal a novel mitochondrial role for KMO, independent from its enzymatic role in the kynurenine pathway.

scholarly journals Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Yan Yu ◽  
Xiao-Dan Peng ◽  
Xiao-Jun Qian ◽  
Kai-Ming Zhang ◽  
Xiang Huang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Structured Illumination ◽  
Structured Illumination Microscopy

AbstractMet tyrosine kinase, a receptor for a hepatocyte growth factor (HGF), plays a critical role in tumor growth, metastasis, and drug resistance. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network. Dysregulated mitochondrial dynamics are responsible for the progression and metastasis of many cancers. Here, using structured illumination microscopy (SIM) and high spatial and temporal resolution live cell imaging, we identified mitochondrial trafficking of receptor tyrosine kinase Met. The contacts between activated Met kinase and mitochondria formed dramatically, and an intact HGF/Met axis was necessary for dysregulated mitochondrial fission and cancer cell movements. Mechanically, we found that Met directly phosphorylated outer mitochondrial membrane protein Fis1 at Tyr38 (Fis1 pY38). Fis1 pY38 promoted mitochondrial fission by recruiting the mitochondrial fission GTPase dynamin-related protein-1 (Drp1) to mitochondria. Fragmented mitochondria fueled actin filament remodeling and lamellipodia or invadopodia formation to facilitate cell metastasis in hepatocellular carcinoma (HCC) cells both in vitro and in vivo. These findings reveal a novel and noncanonical pathway of Met receptor tyrosine kinase in the regulation of mitochondrial activities, which may provide a therapeutic target for metastatic HCC.

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