Important Role of Mitochondria and the Effect of Mood Stabilizers on Mitochondrial Function

Mitochondria primarily serve as source of cellular energy through the Krebs cycle and β-oxidation to generate substrates for oxidative phosphorylation. Redox reactions are used to transfer electrons through a gradient to their final acceptor, oxygen, and to pump hydrogen protons into the intermembrane space. Then, ATP synthase uses the electrochemical gradient to generate adenosine triphosphate (ATP). During these processes, reactive oxygen species (ROS) are generated. ROS are highly reactive molecules with important physiological functions in cellular signaling. Mitochondria play a crucial role in intracellular calcium homeostasis and serve as transient calcium stores. High levels of both, ROS and free cytosolic calcium, can damage mitochondrial and cellular structures and trigger apoptosis. Impaired mitochondrial function has been described in many psychiatric diseases, including mood disorders, in terms of lowered mitochondrial membrane potential, suppressed ATP formation, imbalanced Ca2+ levels and increased ROS levels. In vitro models have indicated that mood stabilizers affect mitochondrial respiratory chain complexes, ROS production, ATP formation, Ca2+ buffering and the antioxidant system. Most studies support the hypothesis that mitochondrial dysfunction is a primary feature of mood disorders. The precise mechanism of action of mood stabilizers remains unknown, but new mitochondrial targets have been proposed for use as mood stabilizers and mitochondrial biomarkers in the evaluation of therapy effectiveness.

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Calcium waves occur as Drosophila oocytes activate

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1420589112 ◽

2015 ◽

Vol 112 (3) ◽

pp. 791-796 ◽

Cited By ~ 59

Author(s):

Taro Kaneuchi ◽

Caroline V. Sartain ◽

Satomi Takeo ◽

Vanessa L. Horner ◽

Norene A. Buehner ◽

...

Keyword(s):

Reproductive Tract ◽

Cytosolic Calcium ◽

Mature Oocyte ◽

Egg Activation ◽

Calcium Wave ◽

Calcium Stores ◽

S Wave ◽

Downstream Signaling ◽

Vitelline Envelope

Egg activation is the process by which a mature oocyte becomes capable of supporting embryo development. In vertebrates and echinoderms, activation is induced by fertilization. Molecules introduced into the egg by the sperm trigger progressive release of intracellular calcium stores in the oocyte. Calcium wave(s) spread through the oocyte and induce completion of meiosis, new macromolecular synthesis, and modification of the vitelline envelope to prevent polyspermy. However, arthropod eggs activate without fertilization: in the insects examined, eggs activate as they move through the female’s reproductive tract. Here, we show that a calcium wave is, nevertheless, characteristic of egg activation in Drosophila. This calcium rise requires influx of calcium from the external environment and is induced as the egg is ovulated. Pressure on the oocyte (or swelling by the oocyte) can induce a calcium rise through the action of mechanosensitive ion channels. Visualization of calcium fluxes in activating eggs in oviducts shows a wave of increased calcium initiating at one or both oocyte poles and spreading across the oocyte. In vitro, waves also spread inward from oocyte pole(s). Wave propagation requires the IP3 system. Thus, although a fertilizing sperm is not necessary for egg activation in Drosophila, the characteristic of increased cytosolic calcium levels spreading through the egg is conserved. Because many downstream signaling effectors are conserved in Drosophila, this system offers the unique perspective of egg activation events due solely to maternal components.

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The Novel Arylamidine T-2307 Selectively Disrupts Yeast Mitochondrial Function by Inhibiting Respiratory Chain Complexes

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00374-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 4

Author(s):

Kohei Yamashita ◽

Taiga Miyazaki ◽

Yoshiko Fukuda ◽

Junichi Mitsuyama ◽

Tomomi Saijo ◽

...

Keyword(s):

Respiratory Chain ◽

Mitochondrial Function ◽

Yeast Cells ◽

Dependent Manner ◽

The Novel ◽

Respiratory Chain Complexes ◽

Content Type ◽

Chain Complexes

ABSTRACT The novel arylamidine T-2307 exhibits broad-spectrum in vitro and in vivo antifungal activities against clinically significant pathogens. Previous studies have shown that T-2307 accumulates in yeast cells via a specific polyamine transporter and disrupts yeast mitochondrial membrane potential. Further, it has little effect on rat liver mitochondrial function. The mechanism by which T-2307 disrupts yeast mitochondrial function is poorly understood, and its elucidation may provide important information for developing novel antifungal agents. This study aimed to determine how T-2307 promotes yeast mitochondrial dysfunction and to investigate the selectivity of this mechanism between fungi and mammals. T-2307 inhibited the respiration of yeast whole cells and isolated yeast mitochondria in a dose-dependent manner. The similarity of the effects of T-2307 and respiratory chain inhibitors on mitochondrial respiration prompted us to investigate the effect of T-2307 on mitochondrial respiratory chain complexes. T-2307 particularly inhibited respiratory chain complexes III and IV not only in Saccharomyces cerevisiae but also in Candida albicans, indicating that T-2307 acts against pathogenic fungi in a manner similar to that of yeast. Conversely, T-2307 showed little effect on bovine respiratory chain complexes. Additionally, we demonstrated that the inhibition of respiratory chain complexes by T-2307 resulted in a decrease in the intracellular ATP levels in yeast cells. These results indicate that inhibition of respiratory chain complexes III and IV is a key factor for selective disruption of yeast mitochondrial function and antifungal activity.

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In situ analysis of mitochondrial respiratory capacity - foundation for cellular physiology

Medicinski pregled ◽

10.2298/mpns1712445g ◽

2017 ◽

Vol 70 (11-12) ◽

pp. 445-448

Author(s):

Enis Garipi ◽

Aleksandra Rakovac ◽

Otto Barak ◽

Damir Lukac ◽

Nada Naumovic ◽

...

Keyword(s):

Mitochondrial Function ◽

Cardiac Tissue ◽

Mitochondrial Enzymes ◽

Respiratory Chain Complexes ◽

Respiratory Capacity ◽

Complex Structural ◽

Human Cardiac Tissue ◽

Novi Sad

Mitochondria are ubiquitous organelles of eukaryotic cells and they are the mayor site of generating energy in the form of adenosine triphoshate through the process of oxidative phosphorylation. Analysis and estimation of mitochondrial function is of outmost importance when it comes to studying intracellular energy metabolism, mechanisms of apoptosis, signaling pathways, calcium storage and the pathophysiology of a large spectrum of human diseases including various neurodegenerative diseases, myopathies, metabolic syndromes and cancer. Respiratory capacity analysis covers one of the many roles that mitochondria play in living cells and it provides us with useful data about functional integrity of mitochondria. Assessment of individual respiratory chain complexes or other mitochondrial enzymes has been widely used to estimate mitochondrial function and dysfunction but it neglects the influence of complex structural and functional interplay of mitochondrial proteins and enzymes and plasmic compounds. Another method that emphasises the importance of studying intact mitochondria is in vitro technique, and although it has many advantages, in some aspects it is far from being representative when it comes to functional assessment of mitochondria. From the perspective of energy production and consumption, the cardiac muscle is a highly demanding tissue and it is the well functioning of mitochondria that is conditio sine qua non for this nature to be fulfilled. In cooperation with the University of Split School of Medicine in Split and under the mentorship of Prof. Marko Ljubkovic, the Department of Physiology of the Faculty of Medicine Novi Sad works on introducing in situ approaches in the analysis of respiratory mitochondrial function in skinned muscle fibers of human cardiac tissue.

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Faculty Opinions recommendation of Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718152193.793485730 ◽

2013 ◽

Author(s):

Hans van Beek

Keyword(s):

Blood Flow ◽

Mitochondrial Function ◽

Brain Metabolism ◽

Deficient Mice

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Major royal jelly proteins prevents NAFLD by improving mitochondrial function and lipid accumulation through activating the AMPK / SIRT3 pathway in vitro

Journal of Food Science ◽

10.1111/1750-3841.15625 ◽

2021 ◽

Author(s):

Xiaochen Zhang ◽

Xinyang Lu ◽

Yingjun Zhou ◽

Xinyu Guo ◽

Yaning Chang

Keyword(s):

Mitochondrial Function ◽

Lipid Accumulation ◽

Royal Jelly

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Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells

Journal of Pineal Research ◽

10.1111/jpi.12728 ◽

2021 ◽

Vol 70 (3) ◽

Author(s):

Bernadetta Bilska ◽

Fiona Schedel ◽

Anna Piotrowska ◽

Joanna Stefan ◽

Michal Zmijewski ◽

...

Keyword(s):

Mitochondrial Function ◽

Melanoma Cells ◽

Human Melanoma ◽

Human Melanoma Cells

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Glycine ameliorates mitochondrial dysfunction caused by ABT-199 in porcine oocytes

Journal of Animal Science ◽

10.1093/jas/skab072 ◽

2021 ◽

Author(s):

Sicong Yu ◽

Lepeng Gao ◽

Yang Song ◽

Xin Ma ◽

Shuang Liang ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Oocyte Maturation ◽

Mitochondrial Function ◽

Protective Action ◽

Damage Model ◽

Developmental Competence ◽

Free Calcium ◽

Maturation In Vitro

Abstract Mitochondria play an important role in controlling oocyte developmental competence. Our previous studies showed that glycine can regulate mitochondrial function and improve oocyte maturation in vitro. However, the mechanisms by which glycine affects mitochondrial function during oocyte maturation in vitro have not been fully investigated. In this study, we induced a mitochondrial damage model in oocytes with the Bcl-2-specific antagonist ABT-199. We investigated whether glycine could reverse the mitochondrial dysfunction induced by ABT-199 exposure and whether it is related to calcium regulation. Our results showed that ABT-199 inhibited cumulus expansion, decreased the oocyte maturation rate and the intracellular glutathione (GSH) level, caused mitochondrial dysfunction, induced oxidative stress, which was confirmed by decreased mitochondrial membrane potential (Δ⍦m) and the expression of mitochondrial function-related genes (PGC-1α), and increased reactive oxygen species (ROS) levels and the expression of apoptosis-associated genes (Bax, caspase-3, CytC). More importantly, ABT-199-treated oocytes showed an increase in the intracellular free calcium concentration ([Ca 2+]i) and had impaired cortical type 1 inositol 1,4,5-trisphosphate receptors (IP3R1) distribution. Nevertheless, treatment with glycine significantly ameliorated mitochondrial dysfunction, oxidative stress and apoptosis, glycine also regulated [Ca 2+]i levels and IP3R1 cellular distribution, which further protects oocyte maturation in ABT-199-induced porcine oocytes. Taken together, our results indicate that glycine has a protective action against ABT-199-induced mitochondrial dysfunction in porcine oocytes.

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158 Inhibition of PI3Kδ improves tumor specific T cell immunity and metabolic fitness

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0158 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A172-A172

Author(s):

Guillermo Rangel Rivera ◽

Guillermo Rangel RIvera ◽

Connor Dwyer ◽

Dimitrios Arhontoulis ◽

Hannah Knochelmann ◽

...

Keyword(s):

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Cell Therapy ◽

Tumor Immunity ◽

Mitochondrial Function ◽

T Cell Differentiation ◽

Tumor Control ◽

T Cell Therapy

BackgroundDurable responses have been observed with adoptive T cell therapy (ACT) in some patients. However, current protocols used to expand T cells often exhibit suboptimal tumor control. Failure in these therapies has been attributed to premature differentiation and impaired metabolism of the infused T cells. Previous work done in our lab showed that reduced PI3Kδ signaling improved ACT. Because PI3Kγ and PI3Kδ have critical regulatory roles in T cell differentiation and function, we tested whether inhibiting PI3Kγ could recapitulate or synergize PI3Kδ blockade.MethodsTo test this, we primed melanoma specific CD8+ pmel-1 T cells, which are specific to the glycoprotein 100 epitope, in the presence of PI3Kγ (IPI-459), PI3Kδ (CAL101 or TGR-1202) or PI3Kγ/δ (IPI-145) inhibitors following antigen stimulation with hgp100, and then infused them into 5Gy total body irradiated B16F10 tumor bearing mice. We characterized the phenotype of the transferred product by flow cytometry and then assessed their tumor control by measuring the tumor area every other day with clippers. For metabolic assays we utilized the 2-NBDG glucose uptake dye and the real time energy flux analysis by seahorse.ResultsSole inhibition of PI3Kδ or PI3Kγ in vitro promoted greater tumor immunity and survival compared to dual inhibition. To understand how PI3Kδ or PI3Kγ blockade improved T cell therapy, we assessed their phenotype. CAL101 treatment produced more CD62LhiCD44lo T cells compared to IPI-459, while TGR-1202 enriched mostly CD62LhiCD44hi T cells. Because decreased T cell differentiation is associated with mitochondrial metabolism, we focused on CAL101 treated T cells to study their metabolism. We found that CAL101 decreased glucose uptake and increased mitochondrial respiration in vitro, indicating augmented mitochondrial function.ConclusionsThese findings indicate that blocking PI3Kδ is sufficient to mediate lasting tumor immunity of adoptively transferred T cells by preventing premature differentiation and improving mitochondrial fitness. Our data suggest that addition of CAL101 to ACT expansion protocols could greatly improve T cell therapies for solid tumors by preventing T cell differentiation and improving mitochondrial function.

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ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron

Cell & Bioscience ◽

10.1186/s13578-021-00563-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tao Liang ◽

Weijian Hang ◽

Jiehui Chen ◽

Yue Wu ◽

Bin Wen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Calcium Transport ◽

Calcium Overload ◽

Mitochondrial Calcium ◽

Mitochondrial Impairment

Abstract Background Apolipoprotein E4 (apoE4) is a major genetic risk factor of Alzheimer’s disease. Its C-terminal-truncated apoE4 (Δ272–299) has neurotoxicity by affecting mitochondrial respiratory function. However, the molecular mechanism(s) underlying the action of apoE4 (Δ272–299) in mitochondrial function remain poorly understood. Methods The impact of neuronal apoE4 (Δ272–299) expression on ER stress, mitochondrial-associated membrane (MAM) formation, GRP75, calcium transport and mitochondrial impairment was determined in vivo and in vitro. Furthermore, the importance of ER stress or GRP75 activity in the apoE4 (Δ272–299)-promoted mitochondrial dysfunction in neuron was investigated. Results Neuronal apoE4 (Δ272–299) expression induced mitochondrial impairment by inducing ER stress and mitochondrial-associated membrane (MAM) formation in vivo and in vitro. Furthermore, apoE4 (Δ272–299) expression promoted GRP75 expression, mitochondrial dysfunction and calcium transport into the mitochondria in neuron, which were significantly mitigated by treatment with PBA (an inhibitor of ER stress), MKT077 (a specific GRP75 inhibitor) or GRP75 silencing. Conclusions ApoE4 (Δ272–299) significantly impaired neuron mitochondrial function by triggering ER stress, up-regulating GRP75 expression to increase MAM formation, and mitochondrial calcium overload. Our findings may provide new insights into the neurotoxicity of apoE4 (Δ272–299) against mitochondrial function and uncover new therapeutic targets for the intervention of Alzheimer’s disease.

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