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 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 Reduced spermatozoa functionality during stress is the consequence of adrenergic-mediated disturbance of mitochondrial dynamics markers

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Isidora M. Starovlah ◽  
Sava M. Radovic Pletikosic ◽  
Tatjana S. Kostic ◽  
Silvana A. Andric
Keyword(s):  
Adrenergic Receptors ◽  
Ex Vivo ◽  
Mitochondrial Dynamics ◽  
Stress Hormones ◽  
Transcriptional Profile ◽  
Stress Signaling ◽  
Human Society ◽  
Repeated Stress ◽  
Β Adrenergic Receptors

Abstract Here we investigate the stress-signaling responsible for the effects of acute/repeated psychological stresses (the most common stresses in human society) on spermatozoa number and functionality, as well as the transcriptional profile of mitochondrial dynamics markers by using the in vivo and ex vivo approaches. Acute and repeated stress inhibit spermatozoa functionality (acute –> 3.2-fold, repeated –> 2.5-fold), while only repeated stress reduces the spermatozoa number (1.7-fold). Stress hormones mimic these effects and decrease the spermatozoa functionality (adrenaline: 10 µM –> 2.4-fold, 100 µM – > 2.8-fold; hydrocortisone: 50 pM –> 2.7-fold, 500 pM –> 8.5-fold). They also significantly disturb the transcriptional profile of all main mitochondrial dynamics markers in spermatozoa. Ex vivo manipulation of stress signaling in spermatozoa reveals that most of these effects are mediated through ɑ1-and/or-β-adrenergic receptors. The transcription of these receptors and their kinases in the same samples is under the significant influence of adrenergic signaling. Our results are the first to show the importance of mitochondrial dynamics markers in spermatozoa since the transcriptional profiles of sixteen-out-of-ninteen are disturbed by manipulation of stress-hormones-signaling. This is a completely new molecular approach to assess spermatozoa functionality and it is important for a better understanding of the correlations between stress, environmental-life-style and other factors, and male (in)fertility.

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 MITOL deletion in the brain impairs mitochondrial structure and ER tethering leading to oxidative stress

2019 ◽  
Vol 2 (4) ◽  
pp. e201900308 ◽  
Author(s):  
Shun Nagashima ◽  
Keisuke Takeda ◽  
Nobuhiko Ohno ◽  
Satoshi Ishido ◽  
Motohide Aoki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Microglial Activation ◽  
Developmental Disorders ◽  
Inflammatory Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Three Dimensional ◽  
Abnormal Behavior ◽  
Mitochondrial Abnormalities

Mitochondrial abnormalities are associated with developmental disorders, although a causal relationship remains largely unknown. Here, we report that increased oxidative stress in neurons by deletion of mitochondrial ubiquitin ligase MITOL causes a potential neuroinflammation including aberrant astrogliosis and microglial activation, indicating that mitochondrial abnormalities might confer a risk for inflammatory diseases in brain such as psychiatric disorders. A role of MITOL in both mitochondrial dynamics and ER-mitochondria tethering prompted us to characterize three-dimensional structures of mitochondria in vivo. In MITOL-deficient neurons, we observed a significant reduction in the ER-mitochondria contact sites, which might lead to perturbation of phospholipids transfer, consequently reduce cardiolipin biogenesis. We also found that branched large mitochondria disappeared by deletion of MITOL. These morphological abnormalities of mitochondria resulted in enhanced oxidative stress in brain, which led to astrogliosis and microglial activation partly causing abnormal behavior. In conclusion, the reduced ER-mitochondria tethering and excessive mitochondrial fission may trigger neuroinflammation through oxidative stress.

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 Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone

2020 ◽  
Author(s):  
Yen-Chi Tsao ◽  
Yu-Jung Chang ◽  
Chun-Hsien Wang ◽  
Linyi Chen
Keyword(s):  
Cancer Progression ◽  
Mitochondrial Dynamics ◽  
Small Cell Lung Carcinoma ◽  
Mitochondrial Fission ◽  
Inhibitory Effect ◽  
Boyden Chamber ◽  
Lawsonia Inermis ◽  
Cell Lung Carcinoma ◽  
Anti Cancer

AbstractIsoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone from Lawsonia inermis and Plumbago europaea, that has been reported to have anti-inflammatory and anti-microbial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anti-cancer effect of chemically-synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer Hela cells by using MTT and Boyden chamber assays. In vivo studies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of NAD(P)H quinone dehydrogenase 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity and thus compromises mitochondrial function. Collectively, this work reveals an anti-cancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function.Chemical compounds: Isoplumbagin (PubChem CID: 375105)

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.

Abstract 20707: Macrophage Mitochondrial Fission is Essential for Continued Clearance of Apoptotic Cells and Plays a Protective Role in Advanced Atherosclerosis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ying Wang ◽  
Ira Tabas ◽  
Masatoshi Nomura
Keyword(s):  
Mitochondrial Dynamics ◽  
Uncoupling Protein ◽  
Mitochondrial Fission ◽  
Myeloid Cell ◽  
Protective Role ◽  
Mitochondrial Fusion ◽  
Apoptotic Cells ◽  
Mitochondrial Dynamic ◽  
Inner Membrane

Introduction: The mitochondrial dynamic processes of fission and fusion influence and integrate with multiple physiologic and pathophysiologic processes. Mitochondrial dynamics dysregulation has been implicated in atherosclerosis, but little is known about the role of myeloid cell specific mitochondrial dynamics in the progression of atherosclerosis. In macrophage-enriched murine atherosclerosis lesion areas, we have found that levels of mitochondrial fission protein DRP1 down-regulated as the lesion progresses. In contrast, the mitochondrial fusion protein MFN2 is up-regulated. Further, mitochondria in lesional macrophages show hyperfusion morphology as the lesion develops. These suggest that mitochondria in macrophages undergo hyperfusion during the lesion progression. Hypothesis: We hypothesize that mitochondrial hyperfusion plays a significant role in atherosclerosis. Methods: We used a model Drp1fl/fl LysmCre+/-Ldlr-/-mice who have hyperfused mitochondria in Mϕs to test the functional significance of mitochondrial hyperfusion in atherosclerosis. Results: We have found that inhibition of Mϕ mitochondrial fission leads to a striking increase of necrotic core area and the accumulation of apoptotic cells, which are likely due to the defective phagocytic clearance of apoptotic cells (efferocytosis) in the advanced stage of atherosclerosis in vivo. This is further verified by another in vivo efferocytosis assay: Drp1fl/fl LysmCre+/-mice are defective of clearing apoptotic thymocytes in vivo. Mechanistically, the continued uptake of apoptotic cellsis impaired in Mϕs with hyperfused mitochondria. This is because of the lower level of uncoupling protein 2 (UCP2), the mitochondrial inner membrane protein that prevents the sustained elevation of inner membrane potential (Δψ). Chemical uncoupler FCCP or restoration of UCP2 can correct the efferocytosis deficiency in DRP1 knockout Mϕs. Conclusions: Macrophage mitochondrial fission is essential for continued clearance of apoptotic cells and plays a protective role in advanced atherosclerosis. This study indicates that mitochondrial fusion/fission could be a novel therapeutic target to prevent lesion necrosis and stabilize the advanced plaques in humans.

Abstract 392: Angiotensin II TypeI Receptor-mediated Mitochondrial Fission and Suppression of Mitophagy Play Crucial Role in Vascular Senescence and Arteriosclerosis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Double Knockout ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Metabolic stress including oxidized low density lipoprotein (ox-LDL) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that undergo quality control by mitochondrial dynamics and mitophagy. This study aims to clarify whether and how mitochondrial dynamics and mitophagy are involved in the etiology of vascular senescence and arteriosclerosis. Methods: VSMC were stimulated by ox-LDL. We also conducted in vivo experiment using C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE mice and Angiotensin II Type1 Receptor (AT1R). Results: Treatment of ox-LDL forced mitochondria to fission through activation of Drp1, induced mitochondrial dysfunction and oxidative stress, and developed cellular senescence. Inhibition of either Drp1, AT1R, MAPK retarded them, suggesting that mitochondrial fission plays key roles to develop premature cellular senescence and is modulated by AT1R/MAPK signal.Administration of ox-LDL decreased the number of mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R signal inhibition increased mitophagy which was not affected by Atg7 knockdown, whereas it was decreased by either Rab9 or Ulk1 knockdown. Immunohistochemistry showed Rab9 dots were co-localized to TOMM20 and LAMP2, whereas LC3 dots were not, suggesting that AT1R signal induces mitophagy through Rab9-dependent alternative autophagy. The degree of vascular senescence was higher, the number of fused mitochondria and mitochondrial function were lower and mitochondrial oxidative stress was higher in ApoE KO than those in WT. DKO attenuated these adverse effect of ApoE KO. Conclusion: AT1R regulates vascular senescence and arteriosclerosis via induction of mitochondrial fission and inhibition of mitophagy.

scholarly journals Dynamin-related protein 1 deficiency impairs mitophagy and accelerates lipopolysaccharide-induced inflammation in mice

2020 ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Masatoshi Nomura ◽  
...  
Keyword(s):  
Liver Disease ◽  
Disease Progression ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Inflammasome Activation ◽  
Disease Development ◽  
Related Protein ◽  
Liver Disease Progression

Abstract Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice. We observed an enhanced inflammatory response accompanied by mitophagy impairment. Drp1 defects directly promoted hepatocyte apoptosis and subsequently induced infiltration of inflammatory macrophages enhanced inflammasome activation in the liver and increased pro-inflammatory cytokine expression in the liver and serum. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. This is a novel mechanism of liver disease development in which Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injure in vivo.

Sign in / Sign up

Export Citation Format

Share Document