scholarly journals Hypobaric Hypoxia Imbalances Mitochondrial Dynamics in Rat Brain Hippocampus

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Khushbu Jain ◽  
Dipti Prasad ◽  
Shashi Bala Singh ◽  
Ekta Kohli
Keyword(s):  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
Hippocampal Neurons ◽  
Hypobaric Hypoxia ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Sprague Dawley ◽  
Neuronal Processes ◽  
Degree Of Association

Brain is predominantly susceptible to oxidative stress and mitochondrial dysfunction during hypobaric hypoxia, and therefore undergoes neurodegeneration due to energy crisis. Evidences illustrate a high degree of association for mitochondrial fusion/fission imbalance and mitochondrial dysfunction. Mitochondrial fusion/fission is a recently reported dynamic mechanism which frequently occurs among cellular mitochondrial network. Hence, the study investigated the temporal alteration and involvement of abnormal mitochondrial dynamics (fusion/fission) along with disturbed mitochondrial functionality during chronic exposure to hypobaric hypoxia (HH). The Sprague-Dawley rats were exposed to simulated high altitude equivalent to 25000 ft for 3, 7, 14, 21, and 28 days. Mitochondrial morphology, distribution within neurons, enzyme activity of respiratory complexes,Δψm, ADP: ATP, and expression of fission/fusion key proteins were determined. Results demonstrated HH induced alteration in mitochondrial morphology by damaged, small mitochondria observed in neurons with disturbance of mitochondrial functionality and reduced mitochondrial density in neuronal processes manifested by excessive mitochondrial fragmentation (fission) and decreased mitochondrial fusion as compared to unexposed rat brain hippocampus. The study suggested that imbalance in mitochondrial dynamics is one of the noteworthy mechanisms occurring in hippocampal neurons during HH insult.

scholarly journals When the Balance Tips: Dysregulation of Mitochondrial Dynamics as a Culprit in Disease

2021 ◽  
Vol 22 (9) ◽  
pp. 4617
Author(s):  
Styliana Kyriakoudi ◽  
Anthi Drousiotou ◽  
Petros P. Petrou
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Disease Development ◽  
Pathological Conditions ◽  
Wide Range

Mitochondria are dynamic organelles, the morphology of which is tightly linked to their functions. The interplay between the coordinated events of fusion and fission that are collectively described as mitochondrial dynamics regulates mitochondrial morphology and adjusts mitochondrial function. Over the last few years, accruing evidence established a connection between dysregulated mitochondrial dynamics and disease development and progression. Defects in key components of the machinery mediating mitochondrial fusion and fission have been linked to a wide range of pathological conditions, such as insulin resistance and obesity, neurodegenerative diseases and cancer. Here, we provide an update on the molecular mechanisms promoting mitochondrial fusion and fission in mammals and discuss the emerging association of disturbed mitochondrial dynamics with human disease.

scholarly journals Interleukin-1β mediates alterations in mitochondrial fusion/fission proteins and memory impairment induced by amyloid-β oligomers

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Andre F. Batista ◽  
Tayná Rody ◽  
Leticia Forny-Germano ◽  
Suzana Cerdeiro ◽  
Maria Bellio ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mitochondrial Dysfunction ◽  
Memory Impairment ◽  
Mitochondrial Dynamics ◽  
Interleukin 1 ◽  
Amyloid Β ◽  
Mitochondrial Fusion ◽  
Synapse Loss ◽  
Cynomolgus Macaques ◽  
The Impact

Abstract Background The lack of effective treatments for Alzheimer’s disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models. Methods We exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1−/−) mice received an i.c.v. infusion of AβOs. Results We report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1−/− mice. Conclusion These findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

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.

scholarly journals Epoxyeicosatrienoic acids pretreatment improves amyloid β-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes

2014 ◽  
Vol 306 (4) ◽  
pp. H475-H484 ◽  
Author(s):  
Pallabi Sarkar ◽  
Ivan Zaja ◽  
Martin Bienengraeber ◽  
Kevin R. Rarick ◽  
Maia Terashvili ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Rat Brain ◽  
Clinical Symptoms ◽  
Mitochondrial Dynamics ◽  
Amyloid Β ◽  
Cellular Respiration ◽  
Epoxyeicosatrienoic Acids ◽  
Hippocampal Astrocytes

Amyloid-β (Aβ) has long been implicated as a causative protein in Alzheimer's disease. Cellular Aβ accumulation is toxic and causes mitochondrial dysfunction, which precedes clinical symptoms of Alzheimer's disease pathology. In the present study, we explored the possible use of epoxyeicosatrienoic acids (EETs), epoxide metabolites of arachidonic acid, as therapeutic target against Aβ-induced mitochondrial impairment using cultured neonatal hippocampal astrocytes. Inhibition of endogenous EET production by a selective epoxygenase inhibitor, MS-PPOH, caused a greater reduction in mitochondrial membrane potential in the presence of Aβ (1, 10 μM) exposure versus absence of Aβ. MS-PPOH preincubation also aggravated Aβ-induced mitochondrial fragmentation. Preincubation of the cells with either 14,15- or 11,12-EET prevented this mitochondrial depolarization and fragmentation. EET pretreatment also further improved the reduction observed in mitochondrial oxygen consumption in the presence of Aβ. Preincubation of the cells with EETs significantly improved cellular respiration under basal condition and in the presence of the protonophore, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP). The uncoupling of ATP synthase from the electron transfer chain that occurred in Aβ-treated cells was also prevented by preincubation with EETs. Lastly, cellular reactive oxygen species production, a hallmark of Aβ toxicity, also showed significant reduction in the presence of EETs. We have previously shown that Aβ reduces EET synthesis in rat brain homogenates and cultured hippocampal astrocytes and neurons (Sarkar P, Narayanan J, Harder DR. Differential effect of amyloid beta on the cytochrome P450 epoxygenase activity in rat brain. Neuroscience 194: 241–249, 2011). We conclude that reduction of endogenous EETs may be one of the mechanisms through which Aβ inflicts toxicity and thus supplementing the cells with exogenous EETs improves mitochondrial dynamics and prevents metabolic impairment.

scholarly journals Mitochondrial Fusion by M1 Promotes Embryoid Body Cardiac Differentiation of Human Pluripotent Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jarmon G. Lees ◽  
Anne M. Kong ◽  
Yi C. Chen ◽  
Priyadharshini Sivakumaran ◽  
Damián Hernández ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryoid Body ◽  
Mitochondrial Dynamics ◽  
Embryoid Bodies ◽  
Mitochondrial Fusion ◽  
Cardiac Differentiation ◽  
Patient Specific ◽  
Mitochondrial Morphology ◽  
Human Ipscs

Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.

scholarly journals Impaired Mitochondrial Fusion and Oxidative Phosphorylation Triggered by High Glucose Is Mediated by Tom22 in Endothelial Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-23 ◽  
Author(s):  
Yi Zeng ◽  
Qi Pan ◽  
Xiaoxia Wang ◽  
Dongxiao Li ◽  
Yajun Lin ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Oxidative Phosphorylation ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
Umbilical Vein ◽  
Vascular Complications ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Atp Production

Much evidence demonstrates that mitochondrial dysfunction plays a crucial role in the pathogenesis of vascular complications of diabetes. However, the signaling pathways through which hyperglycemia leads to mitochondrial dysfunction of endothelial cells are not fully understood. Here, we treated human umbilical vein endothelial cells (HUVECs) with high glucose and examined the role of translocase of mitochondrial outer membrane (Tom) 22 on mitochondrial dynamics and cellular function. Impaired Tom22 expression and protein expression of oxidative phosphorylation (OXPHOS) as well as decreased mitochondrial fusion were observed in HUVECs treated with high glucose. The deletion of Tom22 resulted in reduced mitochondrial fusion and ATP production and increased apoptosis in HUVECs. The overexpression of Tom22 restored the balance of mitochondrial dynamics and OXPHOS disrupted by high glucose. Importantly, we found that Tom22 modulates mitochondrial dynamics and OXPHOS by interacting with mitofusin (Mfn) 1. Taken together, our findings demonstrate for the first time that Tom22 is a novel regulator of both mitochondrial dynamics and bioenergetic function and contributes to cell survival following high-glucose exposure.

scholarly journals Bu-Yin-Qian-Zheng Formula Ameliorates MPP+-Induced Mitochondrial Dysfunction in Parkinson’s Disease via Parkin

2020 ◽  
Vol 11 ◽  
Author(s):  
Hao-Jie Ma ◽  
Cong Gai ◽  
Yuan Chai ◽  
Wan-Di Feng ◽  
Cui-Cui Cheng ◽  
...  
Keyword(s):  
Protein Expression ◽  
Mitochondrial Dysfunction ◽  
Cell Survival ◽  
Mitochondrial Function ◽  
Survival Rates ◽  
Transient Transfection ◽  
Mitochondrial Fusion ◽  
Mitochondrial Morphology ◽  
Protein Levels ◽  
Atp Levels

As a typical traditional Chinese medicine, Bu-Yin-Qian-Zheng Formula (BYQZF) has been shown to have neuroprotective effects in patients with Parkinson’s disease (PD), particularly by ameliorating mitochondrial dysfunction and regulating expression of the parkin protein. However, the underlying mechanisms by which BYQZF affects mitochondrial function through parkin are unclear. Accordingly, in this study, we evaluated the mechanisms by which BYQZF ameliorates mitochondrial dysfunction through parkin in PD. We constructed a parkin-knockdown cell model and performed fluorescence microscopy to observe transfected SH-SY5Y cells. Quantitative real-time reverse transcription polymerase chain reaction and western blotting were conducted to detect the mRNA and protein expression levels of parkin. Additionally, we evaluated the cell survival rates, ATP levels, mitochondrial membrane potential (ΔΨm), mitochondrial morphology, parkin protein expression, PINK1 protein expression, and mitochondrial fusion and fission protein expression after treatment with MPP+ and BYQZF. Our results showed that cell survival rates, ATP levels, ΔΨm, mitochondrial morphology, parkin protein levels, PINK1 protein levels, and mitochondrial fusion protein levels were reduced after MPP+ treatment. In contrast, mitochondrial fission protein levels were increased after MPP+ treatment. Moreover, after transient transfection with a negative control plasmid, the above indices were significantly increased by BYQZF. However, there were no obvious differences in these indices after transient transfection with a parkin-knockdown plasmid. Our findings suggest that BYQZF has protective effects on mitochondrial function in MPP+-induced SH-SY5Y cells via parkin-dependent regulation of mitochondrial dynamics.

scholarly journals Corticotropin-releasing hormone (CRH) alters mitochondrial morphology and function by activating the NF-kB-DRP1 axis in hippocampal neurons

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Chiara R. Battaglia ◽  
Silvia Cursano ◽  
Enrico Calzia ◽  
Alberto Catanese ◽  
Tobias M. Boeckers
Keyword(s):  
Hippocampal Neurons ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Significant Shift ◽  
Corticotropin Releasing Hormone ◽  
Releasing Hormone

AbstractNeuronal stress-adaptation combines multiple molecular responses. We have previously reported that thorax trauma induces a transient loss of hippocampal excitatory synapses mediated by the local release of the stress-related hormone corticotropin-releasing hormone (CRH). Since a physiological synaptic activity relies also on mitochondrial functionality, we investigated the direct involvement of mitochondria in the (mal)-adaptive changes induced by the activation of neuronal CRH receptors 1 (CRHR1). We observed, in vivo and in vitro, a significant shift of mitochondrial dynamics towards fission, which correlated with increased swollen mitochondria and aberrant cristae. These morphological changes, which are associated with increased NF-kB activity and nitric oxide concentrations, correlated with a pronounced reduction of mitochondrial activity. However, ATP availability was unaltered, suggesting that neurons maintain a physiological energy metabolism to preserve them from apoptosis under CRH exposure. Our findings demonstrate that stress-induced CRHR1 activation leads to strong, but reversible, modifications of mitochondrial dynamics and morphology. These alterations are accompanied by bioenergetic defects and the reduction of neuronal activity, which are linked to increased intracellular oxidative stress, and to the activation of the NF-kB/c-Abl/DRP1 axis.

scholarly journals Quantitation of mitochondrial dynamics by photolabeling of individual organelles shows that mitochondrial fusion is blocked during the Bax activation phase of apoptosis

2004 ◽  
Vol 164 (4) ◽  
pp. 493-499 ◽  
Author(s):  
Mariusz Karbowski ◽  
Damien Arnoult ◽  
Hsiuchen Chen ◽  
David C. Chan ◽  
Carolyn L. Smith ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Mitochondrial Dynamics ◽  
Dynamic Balance ◽  
Mitochondrial Fusion ◽  
Confocal Imaging ◽  
Time Range ◽  
Mitochondrial Morphology ◽  
Green Fluorescent ◽  
Mitochondrial Membrane Permeabilization ◽  
Activation Phase

A dynamic balance of organelle fusion and fission regulates mitochondrial morphology. During apoptosis this balance is altered, leading to an extensive fragmentation of the mitochondria. Here, we describe a novel assay of mitochondrial dynamics based on confocal imaging of cells expressing a mitochondrial matrix–targeted photoactivable green fluorescent protein that enables detection and quantification of organelle fusion in living cells. Using this assay, we visualize and quantitate mitochondrial fusion rates in healthy and apoptotic cells. During apoptosis, mitochondrial fusion is blocked independently of caspase activation. The block in mitochondrial fusion occurs within the same time range as Bax coalescence on the mitochondria and outer mitochondrial membrane permeabilization, and it may be a consequence of Bax/Bak activation during apoptosis.

scholarly journals Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0231064
Author(s):  
Yoshitsugu Oikawa ◽  
Rumiko Izumi ◽  
Masashi Koide ◽  
Yoshihiro Hagiwara ◽  
Makoto Kanzaki ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Inclusion Body ◽  
Inclusion Body Myositis ◽  
Mitochondrial Dynamics ◽  
Inflammatory Myopathy ◽  
Idiopathic Inflammatory Myopathy ◽  
Mitochondrial Morphology ◽  
Atp Production ◽  
Bioenergetic Analysis ◽  
Sporadic Inclusion Body Myositis

Sporadic inclusion body myositis (sIBM) is the most common idiopathic inflammatory myopathy, and several reports have suggested that mitochondrial abnormalities are involved in its etiology. We recruited 9 sIBM patients and found significant histological changes and an elevation of growth differential factor 15 (GDF15), a marker of mitochondrial disease, strongly suggesting the involvement of mitochondrial dysfunction. Bioenergetic analysis of sIBM patient myoblasts revealed impaired mitochondrial function. Decreased ATP production, reduced mitochondrial size and reduced mitochondrial dynamics were also observed in sIBM myoblasts. Cell vulnerability to oxidative stress also suggested the existence of mitochondrial dysfunction. Mitochonic acid-5 (MA-5) increased the cellular ATP level, reduced mitochondrial ROS, and provided protection against sIBM myoblast death. MA-5 also improved the survival of sIBM skin fibroblasts as well as mitochondrial morphology and dynamics in these cells. The reduction in the gene expression levels of Opa1 and Drp1 was also reversed by MA-5, suggesting the modification of the fusion/fission process. These data suggest that MA-5 may provide an alternative therapeutic strategy for treating not only mitochondrial diseases but also sIBM.

Sign in / Sign up

Export Citation Format

Share Document