scholarly journals Circadian gene Clock regulates mitochondrial morphology and functions by posttranscriptional way

2018 ◽  
Author(s):  
Lirong Xu ◽  
Qianyun Cheng ◽  
Bingxuan Hua ◽  
Tingting Cai ◽  
Jiaxin Lin ◽  
...  
Keyword(s):  
Circadian Clock ◽  
Posttranscriptional Regulation ◽  
Metabolic Diseases ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Gene ◽  
Mitochondrial Fission ◽  
Strong Relationship ◽  
Mitochondrial Morphology ◽  
Circadian Gene ◽  
Nonalcoholic Fatty Liver

AbstractMany daily activities are under the control of circadian clock, including nutrition metabolism and energy generation. Mitochondria, as the core factories of oxidizing substrates and producing ATP, undergo changes in quantity and morphology to adapt to the demand for energy. It has been demonstrated that mitochondrial gene expression, dynamics and functions are all affected by circadian clock. Here, we demonstrated that circadian gene Clock affects the number, architecture and function of mitochondria via posttranscriptional regulation of Drp1. ClockΔ19 leads to fragmented mitochondria accompanied with the loss of membrane potential, excessive ROS accumulation and decreased mitochondrial respiration and ATP generation. ClockΔ19 mice exhibit disordered lipid metabolism and evident nonalcoholic fatty liver disease (NAFLD), which are rescued by treatment with the mitochondrial fission inhibitor Mdivi-1. These results suggest a strong relationship between Clock, mitochondrial dynamics and metabolic diseases and provide a new perspective on disordered circadian clock and related diseases.

scholarly journals Mitochondrial fission and mitophagy are independent mechanisms regulating ischemia/reperfusion injury in primary neurons

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Anthony R. Anzell ◽  
Garrett M. Fogo ◽  
Zoya Gurm ◽  
Sarita Raghunayakula ◽  
Joseph M. Wider ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Conditional Knockout ◽  
Mitochondrial Morphology ◽  
Primary Neurons ◽  
Mitochondrial Fragmentation

AbstractMitochondrial dynamics and mitophagy are constitutive and complex systems that ensure a healthy mitochondrial network through the segregation and subsequent degradation of damaged mitochondria. Disruption of these systems can lead to mitochondrial dysfunction and has been established as a central mechanism of ischemia/reperfusion (I/R) injury. Emerging evidence suggests that mitochondrial dynamics and mitophagy are integrated systems; however, the role of this relationship in the context of I/R injury remains unclear. To investigate this concept, we utilized primary cortical neurons isolated from the novel dual-reporter mitochondrial quality control knockin mice (C57BL/6-Gt(ROSA)26Sortm1(CAG-mCherry/GFP)Ganl/J) with conditional knockout (KO) of Drp1 to investigate changes in mitochondrial dynamics and mitophagic flux during in vitro I/R injury. Mitochondrial dynamics was quantitatively measured in an unbiased manner using a machine learning mitochondrial morphology classification system, which consisted of four different classifications: network, unbranched, swollen, and punctate. Evaluation of mitochondrial morphology and mitophagic flux in primary neurons exposed to oxygen-glucose deprivation (OGD) and reoxygenation (OGD/R) revealed extensive mitochondrial fragmentation and swelling, together with a significant upregulation in mitophagic flux. Furthermore, the primary morphology of mitochondria undergoing mitophagy was classified as punctate. Colocalization using immunofluorescence as well as western blot analysis revealed that the PINK1/Parkin pathway of mitophagy was activated following OGD/R. Conditional KO of Drp1 prevented mitochondrial fragmentation and swelling following OGD/R but did not alter mitophagic flux. These data provide novel evidence that Drp1 plays a causal role in the progression of I/R injury, but mitophagy does not require Drp1-mediated mitochondrial fission.

scholarly journals High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Qing-Rui Wu ◽  
Dan-Lin Zheng ◽  
Pei-Ming Liu ◽  
Hui Yang ◽  
Lu-An Li ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Calcium Handling ◽  
Cardiomyocyte Hypertrophy ◽  
Mitochondrial Morphology ◽  
Calmodulin Binding ◽  
Downstream Target

AbstractMitochondrial dysfunction and impaired Ca2+ handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca2+ release-activated calcium channel protein 1) calcium channel is important for the increase in Ca2+ entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca2+ influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca2+ entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1–Drp1 axis is a novel target for treating DCM.

Abstract P049: Circadian Clock Dysfunction Impairs Mitochondrial Fitness And Contributes To Myocardial Ischemic Injury

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Inna Rabinovich-Nikitin ◽  
Illana Posen ◽  
Victoria Margulets ◽  
Tami A Martino ◽  
Lorrie A Kirshenbaum
Keyword(s):  
Quality Control ◽  
Cell Viability ◽  
Circadian Clock ◽  
Cardiac Myocytes ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Control Mechanisms ◽  
Complex Activity ◽  
Mitochondrial Dynamic

Cardiac function is highly reliant on mitochondrial oxidative metabolism and fitness. The circadian clock is critically linked to vital physiological process including mitochondrial fission, fusion and quality control mechanisms. However, little is known of how the circadian clock regulates these vital processes in the heart. Herein, we identified a putative circadian Clock - mitochondrial interactome that gates an adaptive stress response for cell viability during myocardial ischemia reperfusion (I-R) injury. We show that Clock transcriptionally coordinates expression of mitochondrial dynamic fusion and fission, bioenergetic and quality control proteins in cardiac myocytes. Transcriptome and gene ontology mapping revealed Clock defective hearts subjected to I-R exhibited major transcriptional deficits in several key survival processes including mitochondrial dynamics, bioenergetics and autophagy that were reduced further following I-R. Gain of function of Clock activity re-established gene transcription of mitochondrial respiratory complex activity, quality control mechanisms and cell viability. Collectively, our data show that mitochondrial fitness and cell survival is mutually dependent upon and obligatorily linked to transcription of the circadian Clock gene in cardiac myocytes. Our data suggest the functional loss of Clock activity predisposes cardiac myocytes to metabolic catastrophe. Hence, therapeutic strategies designed to preserve circadian clock activity in the hearts may prove beneficial in reducing morbidity and mortality following ischemia -related pathologies such as myocardial infarction.

scholarly journals Mitochondrial Dynamics Regulation in Skin Fibroblasts from Mitochondrial Disease Patients

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 450 ◽  
Author(s):  
Takeshi Tokuyama ◽  
Asei Hirai ◽  
Isshin Shiiba ◽  
Naoki Ito ◽  
Keigo Matsuno ◽  
...  
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Myopathy ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
Leigh Syndrome ◽  
Mitochondrial Morphology ◽  
Mitochondrial Fragmentation ◽  
Cellular Toxicity ◽  
Morphologic Changes

Mitochondria are highly dynamic organelles that constantly fuse, divide, and move, and their function is regulated and maintained by their morphologic changes. Mitochondrial disease (MD) comprises a group of disorders involving mitochondrial dysfunction. However, it is not clear whether changes in mitochondrial morphology are related to MD. In this study, we examined mitochondrial morphology in fibroblasts from patients with MD (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and Leigh syndrome). We observed that MD fibroblasts exhibited significant mitochondrial fragmentation by upregulation of Drp1, which is responsible for mitochondrial fission. Interestingly, the inhibition of mitochondrial fragmentation by Drp1 knockdown enhanced cellular toxicity and led to cell death in MD fibroblasts. These results suggest that mitochondrial fission plays a critical role in the attenuation of mitochondrial damage in MD fibroblasts.

scholarly journals Mitochondrial Deficits With Neural and Social Damage in Early-Stage Alzheimer’s Disease Model Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Qingwei Huo ◽  
Sumaiya Tabassum ◽  
Jinxiang Jiang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Morphology ◽  
Therapeutic Interventions ◽  
Early Event ◽  
Mitochondrial Morphology

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide. Mitochondrial dysfunction is thought to be an early event in the onset and progression of AD; however, the precise underlying mechanisms remain unclear. In this study, we investigated mitochondrial proteins involved in organelle dynamics, morphology and energy production in the medial prefrontal cortex (mPFC) and hippocampus (HIPP) of young (1∼2 months), adult (4∼5 months) and aged (9∼10, 12∼18 months) APP/PS1 mice. We observed increased levels of mitochondrial fission protein, Drp1, and decreased levels of ATP synthase subunit, ATP5A, leading to abnormal mitochondrial morphology, increased oxidative stress, glial activation, apoptosis, and altered neuronal morphology as early as 4∼5 months of age in APP/PS1 mice. Electrophysiological recordings revealed abnormal miniature excitatory postsynaptic current in the mPFC together with a minor connectivity change between the mPFC and HIPP, correlating with social deficits. These results suggest that abnormal mitochondrial dynamics, which worsen with disease progression, could be a biomarker of early-stage AD. Therapeutic interventions that improve mitochondrial function thus represent a promising approach for slowing the progression or delaying the onset of AD.

scholarly journals Mitochondrial dynamics and mitophagy are necessary for proper invasive growth in Rice Blast

2019 ◽  
Author(s):  
Yanjun Kou ◽  
Yunlong He ◽  
Jiehua Qiu ◽  
Shu Yazhou ◽  
Fan Yang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Blast Disease ◽  
Cereal Crops ◽  
Mitochondrial Morphology ◽  
Invasive Growth ◽  
In Planta ◽  
Antioxidant Treatment

SUMMARYMagnaporthe oryzaecauses Blast disease, which is one of the most devastating infections in rice and several important cereal crops.M. oryzaeneeds to coordinate gene regulation, morphological changes, nutrient acquisition, and host evasion, in order to invade and proliferate within the plant tissues. Thus far, the molecular mechanisms underlying the regulation of invasive growthin plantahave remained largely unknown. We identified a precise filamentous-punctate-filamentous cycle in mitochondrial morphology duringMagnaporthe-Rice interaction. Interestingly, loss of either the mitochondrial fusion (MoFzo1) or fission (MoDnm1) machinery, or inhibition of mitochondrial fission using Mdivi-1 caused significant reduction inM. oryzaepathogenicity. Furthermore, exogenous carbon source(s) but not antioxidant treatment delayed such mitochondrial dynamics/transition during invasive growth. Such nutrient-based regulation of organellar dynamics preceded MoAtg24-mediated mitophagy, which was found to be essential for proper biotrophic development and invasive growthin planta. We propose that precise mitochondrial dynamics and mitophagy occur during the transition from biotrophy to necrotrophy, and are required for proper induction and establishment of the blast disease in rice.

scholarly journals Novel regulatory roles of Mff and Drp1 in E3 ubiquitin ligase MARCH5–dependent degradation of MiD49 and Mcl1 and control of mitochondrial dynamics

2017 ◽  
Vol 28 (3) ◽  
pp. 396-410 ◽  
Author(s):  
Edward Cherok ◽  
Shan Xu ◽  
Sunan Li ◽  
Shweta Das ◽  
W. Alex Meltzer ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Critical Role ◽  
E3 Ubiquitin Ligase ◽  
Mitochondrial Morphology ◽  
Ubiquitinated Proteins ◽  
Terminal Domain ◽  
Degradation Rates ◽  
And Control

MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5’s activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1. Effects of Mff and Drp1 depletion on degradation rates and ubiquitination of Mcl1 and MiD49 were eliminated in Drp1−/−/MARCH5−/− and Mff−/−/MARCH5−/− cells. Our data show that it is not mitochondrial morphology per se but rather Mff and Drp1 that directly control MARCH5. Consistently, we find that Mff is an integral component of the MARCH5/p97/Npl4 complex, which is also controlled by MARCH5’s C-terminal domain. Furthermore, not only mitochondrial fission but also fusion is regulated through Mff and Drp1 protein activities. Thus, in addition to their canonical roles in mitochondrial fission, Mff and Drp1 also act as regulatory factors that control mitochondrial fission and fusion.

Abstract 393: MCL-1 Promotes Survival and Influences Mitochondrial Dynamics in Cardiac Myocytes

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Alexandra G Moyzis ◽  
Robert L Thomas ◽  
Jennifer Kuo ◽  
Åsa B Gustafsson
Keyword(s):  
Cell Death ◽  
Cardiac Myocytes ◽  
Apoptotic Cell ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Apoptotic Cell Death ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Morphology ◽  
Rapid Degradation

The BCL-2 family proteins are important regulators of mitochondrial structure and integrity. MCL-1 is an anti-apoptotic BCL-2 protein that is highly expressed in the myocardium compared to the other anti-apoptotic proteins BCL-2 and BCL-X L. Recently, we reported that MCL-1 is essential for myocardial homeostasis. Cardiac-specific deletion of MCL-1 in mice led to rapid mitochondrial dysfunction, hypertrophy, and lethal cardiomyopathy. Surprisingly, MCL-1 deficient myocytes did not undergo apoptotic cell death. Instead, the cells displayed signs of mitochondrial deterioration and necrotic cell death, suggesting that MCL-1 has an additional role in maintaining mitochondrial function in cardiac myocytes. Similarly, deletion of MCL-1 in fibroblasts caused rapid mitochondrial fragmentation followed by cell death at 72 hours. Interestingly, the MCL-1 deficient fibroblasts retained cytochrome c in the mitochondria , confirming that the cells were not undergoing apoptotic cell death. We have also identified that MCL-1 localizes to the mitochondrial outer membrane (OM) and the matrix in the myocardium and that the two forms respond differently to stress. MCL-1 OM was rapidly degraded after myocardial infarction or fasting, whereas MCL-1 Matrix levels were maintained. Similarly, starvation of MEFs resulted in rapid degradation of MCL-1 OM , whereas MCL-1 Matrix showed delayed degradation. Treatment with the mitochondrial uncoupler FCCP led to rapid degradation of both forms. This suggests that the susceptibility to degradation is dependent on its localization and the nature of the stress. Our data also suggests that these two forms perform distinct functions in regulating mitochondrial morphology and survival. Overexpression of MCL-1 Matrix promoted mitochondrial fusion in fibroblasts under baseline conditions and protected cells against FCCP-mediated mitochondrial fission and clearance by autophagosomes. Thus, our data suggest that MCL-1 exists in two separate locations where it performs different functions. MCL-1 Matrix promotes mitochondrial fusion, which protects cells against excessive mitochondrial clearance during unfavorable conditions.

scholarly journals Dynamin-related protein 1 mediates low glucose-induced endothelial dysfunction in human arterioles

2017 ◽  
Vol 312 (3) ◽  
pp. H515-H527 ◽  
Author(s):  
Michael J. Tanner ◽  
Jingli Wang ◽  
Rong Ying ◽  
Tisha B. Suboc ◽  
Mobin Malik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Cardiovascular Complications ◽  
Mitochondrial Morphology ◽  
Vascular Relaxation ◽  
Mitochondrial Fragmentation ◽  
Low Glucose

Intensive glycemic regulation has resulted in an increased incidence of hypoglycemia. Hypoglycemic burden correlates with adverse cardiovascular complications and contributes acutely and chronically to endothelial dysfunction. Prior data indicate that mitochondrial dysfunction contributes to hypoglycemia-induced endothelial dysfunction, but the mechanisms behind this linkage remain unknown. We attempt to determine whether clinically relevant low-glucose (LG) exposures acutely induce endothelial dysfunction through activation of the mitochondrial fission process. Characterization of mitochondrial morphology was carried out in cultured endothelial cells by using confocal microscopy. Isolated human arterioles were used to explore the effect LG-induced mitochondrial fission has on the formation of detrimental reactive oxygen species (ROS), bioavailability of nitric oxide (NO), and endothelial-dependent vascular relaxation. Fluorescence microscopy was employed to visualize changes in mitochondrial ROS and NO levels and videomicroscopy applied to measure vasodilation response. Pharmacological disruption of the profission protein Drp1 with Mdivi-1 during LG exposure reduced mitochondrial fragmentation among vascular endothelial cells (LG: 0.469; LG+Mdivi-1: 0.276; P = 0.003), prevented formation of vascular ROS (LG: 2.036; LG+Mdivi-1: 1.774; P = 0.005), increased the presence of NO (LG: 1.352; LG+Mdivi-1: 1.502; P = 0.048), and improved vascular dilation response to acetylcholine (LG: 31.6%; LG+Mdivi-1; 78.5% at maximum dose; P < 0.001). Additionally, decreased expression of Drp1 via siRNA knockdown during LG conditions also improved vascular relaxation. Exposure to LG imparts endothelial dysfunction coupled with altered mitochondrial phenotypes among isolated human arterioles. Disruption of Drp1 and subsequent mitochondrial fragmentation events prevents impaired vascular dilation, restores mitochondrial phenotype, and implicates mitochondrial fission as a primary mediator of LG-induced endothelial dysfunction. NEW & NOTEWORTHY Acute low-glucose exposure induces mitochondrial fragmentation in endothelial cells via Drp1 and is associated with impaired endothelial function in human arterioles. Targeting of Drp1 prevents fragmentation, improves vasofunction, and may provide a therapeutic target for improving cardiovascular complications among diabetics. Listen to this article’s corresponding podcast @ http://ajpheart.podbean.com/e/mitochondrial-dynamics-impact-endothelial-function/ .

scholarly journals Mitochondrial Dynamics: In Cell Reprogramming as It Is in Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Javier Prieto ◽  
Josema Torres
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Somatic Cells ◽  
Embryonic Stem ◽  
Cellular Transformation ◽  
Cell Reprogramming ◽  
Mitochondrial Morphology ◽  
Pluripotent Cells

Somatic cells can be reprogrammed into a pluripotent cellular state similar to that of embryonic stem cells. Given the significant physiological differences between the somatic and pluripotent cells, cell reprogramming is associated with a profound reorganization of the somatic phenotype at all levels. The remodeling of mitochondrial morphology is one of these dramatic changes that somatic cells have to undertake during cell reprogramming. Somatic cells transform their tubular and interconnected mitochondrial network to the fragmented and isolated organelles found in pluripotent stem cells early during cell reprogramming. Accordingly, mitochondrial fission, the process whereby the mitochondria divide, plays an important role in the cell reprogramming process. Here, we present an overview of the importance of mitochondrial fission in both cell reprogramming and cellular transformation.

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