scholarly journals Ndufs4 ablation decreases synaptophysin expression in hippocampus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Subrata Kumar Shil ◽  
Yoshiteru Kagawa ◽  
Banlanjo Abdulaziz Umaru ◽  
Fumika Nanto-Hara ◽  
Hirofumi Miyazaki ◽  
...  
Keyword(s):  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Activity ◽  
Mitochondrial Complex ◽  
Neuronal Function ◽  
Mouse Hippocampus ◽  
Extracellular Regulated Kinase ◽  
Presynaptic Protein

AbstractAltered function of mitochondrial respiratory chain in brain cells is related to many neurodegenerative diseases. NADH Dehydrogenase (Ubiquinone) Fe-S protein 4 (Ndufs4) is one of the subunits of mitochondrial complex I and its mutation in human is associated with Leigh syndrome. However, the molecular biological role of Ndufs4 in neuronal function is poorly understood. In this study, upon Ndufs4 expression confirmation in NeuN-positive neurons, and GFAP-positive astrocytes in WT mouse hippocampus, we found significant decrease of mitochondrial respiration in Ndufs4-KO mouse hippocampus. Although there was no change in the number of NeuN positive neurons in Ndufs4-KO hippocampus, the expression of synaptophysin, a presynaptic protein, was significantly decreased. To investigate the detailed mechanism, we silenced Ndufs4 in Neuro-2a cells and we observed shorter neurite lengths with decreased expression of synaptophysin. Furthermore, western blot analysis for phosphorylated extracellular regulated kinase (pERK) revealed that Ndufs4 silencing decreases the activity of ERK signalling. These results suggest that Ndufs4-modulated mitochondrial activity may be involved in neuroplasticity via regulating synaptophysin expression.

scholarly journals The Role of Mitochondrial Calcium Homeostasis in Alzheimer’s and Related Diseases

2020 ◽  
Vol 21 (23) ◽  
pp. 9153
Author(s):  
Kerry C. Ryan ◽  
Zahra Ashkavand ◽  
Kenneth R. Norman
Keyword(s):  
Neurodegenerative Diseases ◽  
Calcium Signaling ◽  
Mitochondrial Function ◽  
Reciprocal Relationship ◽  
Mitochondrial Activity ◽  
Mitochondrial Calcium ◽  
Protein Homeostasis ◽  
Neuronal Function ◽  
The Impact

Calcium signaling is essential for neuronal function, and its dysregulation has been implicated across neurodegenerative diseases, including Alzheimer’s disease (AD). A close reciprocal relationship exists between calcium signaling and mitochondrial function. Growing evidence in a variety of AD models indicates that calcium dyshomeostasis drastically alters mitochondrial activity which, in turn, drives neurodegeneration. This review discusses the potential pathogenic mechanisms by which calcium impairs mitochondrial function in AD, focusing on the impact of calcium in endoplasmic reticulum (ER)–mitochondrial communication, mitochondrial transport, oxidative stress, and protein homeostasis. This review also summarizes recent data that highlight the need for exploring the mechanisms underlying calcium-mediated mitochondrial dysfunction while suggesting potential targets for modulating mitochondrial calcium levels to treat neurodegenerative diseases such as AD.

scholarly journals Mitochondrial retrograde signaling regulates neuronal function

2015 ◽  
Vol 112 (44) ◽  
pp. E6000-E6009 ◽  
Author(s):  
Umut Cagin ◽  
Olivia F. Duncan ◽  
Ariana P. Gatt ◽  
Marc S. Dionne ◽  
Sean T. Sweeney ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Hypoxia Inducible Factor ◽  
Leigh Syndrome ◽  
Retrograde Signaling ◽  
Neuronal Function ◽  
Mitochondrial Retrograde Signaling ◽  
Factor Alpha ◽  
Familial Parkinson’S Disease ◽  
Mitochondrial Defect

Mitochondria are key regulators of cellular homeostasis, and mitochondrial dysfunction is strongly linked to neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Mitochondria communicate their bioenergetic status to the cell via mitochondrial retrograde signaling. To investigate the role of mitochondrial retrograde signaling in neurons, we induced mitochondrial dysfunction in the Drosophila nervous system. Neuronal mitochondrial dysfunction causes reduced viability, defects in neuronal function, decreased redox potential, and reduced numbers of presynaptic mitochondria and active zones. We find that neuronal mitochondrial dysfunction stimulates a retrograde signaling response that controls the expression of several hundred nuclear genes. We show that the Drosophila hypoxia inducible factor alpha (HIFα) ortholog Similar (Sima) regulates the expression of several of these retrograde genes, suggesting that Sima mediates mitochondrial retrograde signaling. Remarkably, knockdown of Sima restores neuronal function without affecting the primary mitochondrial defect, demonstrating that mitochondrial retrograde signaling is partly responsible for neuronal dysfunction. Sima knockdown also restores function in a Drosophila model of the mitochondrial disease Leigh syndrome and in a Drosophila model of familial Parkinson’s disease. Thus, mitochondrial retrograde signaling regulates neuronal activity and can be manipulated to enhance neuronal function, despite mitochondrial impairment.

Advanced glycation end product accumulation in rho0 cells without a functional respiratory chain

2009 ◽  
Vol 390 (9) ◽  
Author(s):  
Norbert Nass ◽  
Alexandra Kukat ◽  
Peter Seibel ◽  
Hans-Jürgen Brömme ◽  
Reinhard Schinzel ◽  
...  
Keyword(s):  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Total Protein Content ◽  
Mitochondrial Activity ◽  
Cell Fractionation ◽  
Osteosarcoma Cell ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
Product Accumulation

Abstract Advanced glycation end products (AGEs) accumulate during ageing with reactive oxygen species from the mitochondrial respiratory chain discussed as a driving force. To determine the role of mitochondrial activity for AGE formation, a rho0 derivative of the 143B.TK- osteosarcoma cell line lacking the respiratory chain, was analysed. These cells exhibit decreased superoxide formation but unchanged mitochondrial SOD expression as well as unchanged antioxidative free sulfhydryl (SH) levels. Whereas total protein content shows no differences in AGE levels, cell fractionation and Western blotting demonstrates some changes in the AGE pattern. Thus, the absence of functional respiration has only a negligible impact on AGE accumulation.

scholarly journals Deactivation of mitochondrial complex I after hypoxia–ischemia in the immature brain

2018 ◽  
Vol 39 (9) ◽  
pp. 1790-1802 ◽  
Author(s):  
Anna Stepanova ◽  
Csaba Konrad ◽  
Sergio Guerrero-Castillo ◽  
Giovanni Manfredi ◽  
Susan Vannucci ◽  
...  
Keyword(s):  
Complex I ◽  
Mitochondrial Respiratory Chain ◽  
Mitochondrial Complex I ◽  
Ros Production ◽  
Mitochondrial Complex ◽  
Immature Brain ◽  
Mitochondrial Oxygen Consumption ◽  
Mitochondrial Target ◽  
Enzyme Complexes

Mortality from perinatal hypoxic–ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on H2O2 release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome c oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy.

scholarly journals Coenzyme Q10 and Immune Function: An Overview

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 759
Author(s):  
David Mantle ◽  
Robert A. Heaton ◽  
Iain P. Hargreaves
Keyword(s):  
Immune System ◽  
Immune Function ◽  
Coenzyme Q10 ◽  
Mitochondrial Respiratory Chain ◽  
Inflammatory Gene Expression ◽  
Optimal Functioning ◽  
Human Immune ◽  
Coq10 Supplementation ◽  
Lipid Soluble Antioxidant

Coenzyme Q10 (CoQ10) has a number of important roles in the cell that are required for optimal functioning of the immune system. These include its essential role as an electron carrier in the mitochondrial respiratory chain, enabling the process of oxidative phosphorylation to occur with the concomitant production of ATP, together with its role as a potential lipid-soluble antioxidant, protecting the cell against free radical-induced oxidation. Furthermore, CoQ10 has also been reported to have an anti-inflammatory role via its ability to repress inflammatory gene expression. Recently, CoQ10 has also been reported to play an important function within the lysosome, an organelle central to the immune response. In view of the differing roles CoQ10 plays in the immune system, together with the reported ability of CoQ10 supplementation to improve the functioning of this system, the aim of this article is to review the current literature available on both the role of CoQ10 in human immune function and the effect of CoQ10 supplementation on this system.

scholarly journals Neurons and Glia Interplay in α-Synucleinopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4994
Author(s):  
Panagiota Mavroeidi ◽  
Maria Xilouri
Keyword(s):  
Glial Cells ◽  
Current Knowledge ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions ◽  
Glial Function ◽  
Presynaptic Protein

Accumulation of the neuronal presynaptic protein alpha-synuclein within proteinaceous inclusions represents the key histophathological hallmark of a spectrum of neurodegenerative disorders, referred to by the umbrella term a-synucleinopathies. Even though alpha-synuclein is expressed predominantly in neurons, pathological aggregates of the protein are also found in the glial cells of the brain. In Parkinson’s disease and dementia with Lewy bodies, alpha-synuclein accumulates mainly in neurons forming the Lewy bodies and Lewy neurites, whereas in multiple system atrophy, the protein aggregates mostly in the glial cytoplasmic inclusions within oligodendrocytes. In addition, astrogliosis and microgliosis are found in the synucleinopathy brains, whereas both astrocytes and microglia internalize alpha-synuclein and contribute to the spread of pathology. The mechanisms underlying the pathological accumulation of alpha-synuclein in glial cells that under physiological conditions express low to non-detectable levels of the protein are an area of intense research. Undoubtedly, the presence of aggregated alpha-synuclein can disrupt glial function in general and can contribute to neurodegeneration through numerous pathways. Herein, we summarize the current knowledge on the role of alpha-synuclein in both neurons and glia, highlighting the contribution of the neuron-glia connectome in the disease initiation and progression, which may represent potential therapeutic target for a-synucleinopathies.

scholarly journals Role of cysteine in regulating morphogenesis and mitochondrial activity in the dimorphic fungus Histoplasma capsulatum.

1981 ◽  
Vol 78 (7) ◽  
pp. 4596-4600 ◽  
Author(s):  
B. Maresca ◽  
A. M. Lambowitz ◽  
V. B. Kumar ◽  
G. A. Grant ◽  
G. S. Kobayashi ◽  
...  
Keyword(s):  
Histoplasma Capsulatum ◽  
Mitochondrial Activity ◽  
Dimorphic Fungus

scholarly journals TAT-Conjugated NDUFS8 Can Be Transduced into Mitochondria in a Membrane-Potential-Independent Manner and Rescue Complex I Deficiency

2021 ◽  
Vol 22 (12) ◽  
pp. 6524
Author(s):  
Bo-Yu Lin ◽  
Gui-Teng Zheng ◽  
Kai-Wen Teng ◽  
Juan-Yu Chang ◽  
Chao-Chang Lee ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Fusion Proteins ◽  
Complex I ◽  
Nadh Dehydrogenase ◽  
Leigh Syndrome ◽  
Protein Transduction ◽  
Independent Manner ◽  
Complex I Deficiency ◽  
Transactivator Of Transcription ◽  
Hiv 1

NADH dehydrogenase (ubiquinone) Fe-S protein 8 (NDUFS8) is a nuclear-encoded core subunit of human mitochondrial complex I. Defects in NDUFS8 are associated with Leigh syndrome and encephalomyopathy. Cell-penetrating peptide derived from the HIV-1 transactivator of transcription protein (TAT) has been successfully applied as a carrier to bring fusion proteins into cells without compromising the biological function of the cargoes. In this study, we developed a TAT-mediated protein transduction system to rescue complex I deficiency caused by NDUFS8 defects. Two fusion proteins (TAT-NDUFS8 and NDUFS8-TAT) were exogenously expressed and purified from Escherichia coli for transduction of human cells. In addition, similar constructs were generated and used in transfection studies for comparison. The results showed that both exogenous TAT-NDUFS8 and NDUFS8-TAT were delivered into mitochondria and correctly processed. Interestingly, the mitochondrial import of TAT-containing NDUFS8 was independent of mitochondrial membrane potential. Treatment with TAT-NDUFS8 not only significantly improved the assembly of complex I in an NDUFS8-deficient cell line, but also partially rescued complex I functions both in the in-gel activity assay and the oxygen consumption assay. Our current findings suggest the considerable potential of applying the TAT-mediated protein transduction system for treatment of complex I deficiency.

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