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Implication of Mitochondrial Coenzyme Q10 (Ubiquinone) in Alzheimer’s Disease *
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Sayantan Maitra, Dibyendu Dutta
Mitochondria that are present in synapses of neurons produce ATP and buffer Ca2+ ion concentration, both fundamental processes for the implementation of neurotransmission and generation of membrane potential along the axon [34,35]. Both non-synaptic and synaptic mitochondria are usually synthesized in the neuronal soma and then transported in the other area of the neurons where they are required. Transportation of mitochondria along the axons is attributed to microtubules, and it requires motor proteins such as kinesin, dynein, as well as the OMM protein mitochondrial rho GTPase (Miro). Axonal transport of mitochondria is also influenced by the metabolic demand and the Ca2+ status at the synaptic level [36]. Formation of contact sites between endoplasmic reticulum (ER) and mitochondria facilitates the uptake of Ca2+ from the cytosol [37]. There are two types of Ca2+ channels present in the mitochondria, namely, the mitochondria calcium uniporter (MCU) expressed in the IMM and the voltage-dependent anion channel (VDAC) localized in the OMM that regulates the release of the Ca2+ ions from the mitochondria. Additionally, VDAC cooperates with the adenine nucleotide transporter in the IMM and the cyclophilin D (CypD) in the matrix in order to form the mitochondrial permeability transition pore (mPTP). An mPTP opening leads to the activation of apoptosis and then cell death [38].
Introduction to lactic acidemias
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Mitochondrial proteins synthesized in the cytosol must be transported into the mitochondria. Defects in the transport proteins could provide another novel mechanism of the pathogenesis of mitochondrial disease. Two of these protein complexes, translocation outer mitochondrial membrane (TOMM) and translocation inner mitochondrial membrane (TIMM), have been extensively studied in yeast in which the genes have been characterized. The human gene encoding an ortholog of TOMM 20 has been identified [24], and the human genome project has made the genes for other orthologs available. A search for abnormalities causing human disease is under way. Among the transporters of the mitochondria is an outer membrane transporter known as voltage-dependent ion channel (VDAC) and also known as mitochondrial porin, because it forms a pore, opening the membrane for anions like phosphate, chloride, and adenine nucleotides at low transmembrane voltage; at high voltage, it forms a channel for cations and uncharged molecules. A deficiency in VDAC has been reported in Western blot studies [25] in a patient with impaired myopathy and impaired oxidation of pyruvate in mitochondria of muscle. Lactate was elevated only mildly after 2 g/kg of glucose.
Mitochondrial Dysfunction and Heart Diseases
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
In addition to the roles in regulation of ROS and acetylation (Figure 3), mitochondria are capable of directly and rapidly taking up calcium, affecting both matrix energetics within mitochondria or releasing Ca2+ into cytosol. Ca2+ import across the outer mitochondrial membrane occurs via the voltage-dependent anion channels (VDAC).125 VDAC is as a large voltage-gated channel, fully opened with high-conductance and low anion-selectivity at low transmembrane potentials (less than 20–30 mV), but switching to high cation selectivity and lower conductance at higher potentials.126–128 Ca2+ transport across the inner mitochondrial membrane occurs through two possible mechanisms: First, through mitochondrial calcium uniporter (MCU), which transfers Ca2+ down the potential gradient generated during oxidative phosphorylation. Pharmacological inhibition of MCU with Ru360 has been reported to reduce the incidence of ventricular arrhythmias induced by ischemia–reperfusion in the rat heart.129 Second, through a Na+/Ca2+ exchanger and a H+/Ca2+ exchanger. During pathological conditions a large increase in mitochondrial calcium levels is thought to activate the mitochondrial permeability transition pore, resulting in cell death.
Targeting glucose metabolism to develop anticancer treatments and therapeutic patents
Published in Expert Opinion on Therapeutic Patents, 2022
Yan Zhou, Yizhen Guo, Kin Yip Tam
HK1 and HK2 bind to mitochondria through the interaction with VDAC and play an important role in the stability of the mitochondrial environment [12]. The upregulation of HK2 protein levels is required to maintain a high glycolytic environment in aggressive cancer cells. About 80% of HK2 is related to mitochondria through interaction with VDAC in cancer cells. The mitochondrial-bound HK2 can obtain the ATP required for glucose phosphorylation to accelerate the glycolysis pace [13]. The interaction between VDAC and HK2 on the outer mitochondrial membrane (OMM) down-regulates the apoptotic activity by inhibiting the translocation of cytochrome c to cytoplasm [14]. VDAC increases the connection between HK2 and the mitochondria of cancer cells [15]. VDAC has the privilege to obtain mitochondrial ATP and regulate the opening of mitochondrial permeability transition pores, leading to the resistance of cancer cells to apoptosis. The transfer of HK2 from the cytoplasm to OMM in cancer cells, coupled with its important role in the glycolytic pathway, makes HK2 a promising target for the development of anticancer treatments [16].
Iron-deficient diet induces distinct protein profile related to energy metabolism in the striatum and hippocampus of adult rats
Published in Nutritional Neuroscience, 2022
Jessica M. V. Pino, Erika S. Nishiduka, Márcio H. M. da Luz, Vitória F. Silva, Hanna K. M. Antunes, Alexandre K. Tashima, Pedro L. R. Guedes, Altay A. L. de Souza, Kil S. Lee
In the hippocampus of the IR group, transketolase (TKT) and alpha-enolase (ENO1) were increased (Figure 3, right panel and Table S3). This pattern can occur when glucose metabolism via the pentose-phosphate pathway is increased. The IR diet also altered enzymes that participate in the astrocyte-neuron lactate shuttle mechanism that includes L-lactate dehydrogenase (LDHB), aspartate aminotransferase (GOT2), glutamine synthetase (GLUL), sodium/potassium-transporting ATPase (ATP1A2), vesicular glutamate transporter 1 (SLC17A7) and excitatory amino acid transporter 2 (SLC1A2) (Figure 3, right panel and Table S3). In Figure 3, these alterations were schematized in a single cell, but some of these alterations can be specific to neurons or astrocytes [20]. The hippocampus of IR group also showed increased levels of succinate dehydrogenase flavoprotein (SDHA) and cytochrome b-c1 complex subunit 8 (UQCRQ), and reduced levels of NADH dehydrogenase iron-sulfur protein 2 (NDFS2), cytochrome c oxidase subunit 2 (MTCO2) and ATP synthase subunit β (ATP5B) (Figure 3, right panel and Table S3). These proteins are components of the electron transport chain. We also observed increased molecular chaperons such as calnexin (CANX), DnaJ homolog subfamily C member 5 (DNAJC5) and heat shock protein 90 (HSP90AB1). As in the striatum, VDAC was decreased in the hippocampus of the IR group, but a reduction of Parkinson disease protein 7 (PARK7) and alpha-synuclein (SNCA) was observed only in the hippocampus of the IR group (Figure 3, right panel and Table S3). These proteins are closely linked to Parkinson's disease.
Investigation of the effects of cannabidiol on vacuous chewing movements, locomotion, oxidative stress and blood glucose in rats treated with oral haloperidol
Published in The World Journal of Biological Psychiatry, 2020
Jaiyeola Abiola Kajero, Soraya Seedat, Jude Ohaeri, Abidemi Akindele, Oluwagbemiga Aina
Ion channels are known to be involved in the pathophysiology of movement disorders. There is evidence that CBD changes the conductance of voltage-dependent anion channels (VDAC1) (Rimmerman et al. 2013). VDAC is required for the degradation of mitochondria which causes the loss of dopaminergic neurons seen in Parkinson’s disease (PD), VDAC may therefore be involved in the effect of CBD on movement disorders (Geisler et al. 2010; Ibeas Bih et al. 2015). CBD has also been shown to be involved in the activation and upregulation of Peroxisome Proliferator-activated Receptors (PPARγ), a receptor known to be involved in oral dyskinesia (O’Sullivan et al. 2009; Stone et al. 2009; Ramer et al. 2013). Voltage-gated calcium channels (VGCC) may also be involved in the pathophysiology of tremors and they are also blocked by CBD at low doses (Bourin and Nic Dhonnchadha 2005; Ross et al. 2008; Ibeas Bih et al. 2015). The receptors targeted by CBD to improve movement disorders includes 5HT1A and 5HT2A subtypes in the basal ganglia (Russo et al. 2005), CBD is believed to interact with these subtypes to ameliorate the dysfunction of the dopaminergic system seen in TD (Russo et al. 2005; Gomes et al. 2013; Ibeas Bih et al. 2015). CBD is also a strong antagonist at cholinergic receptors Α4β2and α7 nAchRs (Mahgoub et al. 2013). These receptors are implicated in acute dyskinesia because their rapid desensitisation reduces dyskinesia (Henry et al. 2001). The above may also contribute to the effects of CBD on movement disorders in our study.