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Mitochondrial Dysfunction and Hearing Loss
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Aetiology: There is a deficiency of VDAC1 (voltage-dependent anion channel-1) in skeletal muscle and fibroblasts. The VDAC1 protein is a transporter for metabolites directly involved in oxidative phosphorylation. In other cases other mitochondrial membrane carriers have been reported, ATN (SLC25A4) causing PEOA2 and defects in SLC25A20 producing metabolic problems.35,36
Mitochondrial Dysfunction in Chronic Disease
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Christopher Newell, Heather Leduc-Pessah, Aneal Khan, Jane Shearer
Apoptosis, or programmed cell death, is the process of cell turnover in a controlled manner. In mitochondrial-mediated necrotic cell death, the mitochondrial permeability transition pore (MPTP) initiates mitochondrial membrane permeabilization (67). The prolonged release of calcium, ROS, and other stimuli lead to MPTP opening and eventual mitochondrial membrane permeabilization, which results in cell rupture from a lack of cell membrane integrity (67). Differing from necrosis, apoptosis involves characteristic morphologic changes which culminate in the formation of apoptotic bodies – budding cellular fragments consisting of cytoplasm with tightly packed organelles which may contain a nuclear fragment (36). These apoptotic bodies are then targeted for breakdown by phagocytotic cells in the absence of further damaging responses to the neighbouring cellular populations (139). Characterized into intrinsic or extrinsic pathways, intrinsic refers to apoptosis activation by intracellular signals and protein release from the mitochondrial intermembrane space, while extrinsic refers to the role of extracellular ligands inducing apoptosis (36). Acting in response to mtDNA damage, metabolic stress accumulation, nDNA damage, and other cellular cues, the intrinsic apoptotic pathway can be initiated by permeabilization of the OMM. Associated with dissipation of mitochondrial membrane potential, pores in the OMM enable pro-apoptotic mediators to leak out (43). These pores are created by oligomerization of voltage-dependent anion channel 1 (VDAC1), the most abundant mitochondrial OMM protein (15). VDAC1 helps to regulate apoptosis through interaction with the pro-apoptotic Bcl-2 family of proteins and the anti-apoptotic hexokinase enzyme (15).
Chondrocyte protein co-synthesis network analysis links ECM mechanosensing to metabolic adaptation in osteoarthritis
Published in Expert Review of Proteomics, 2021
Aspasia Destouni, Konstantinos C. Tsolis, Anastassios Economou, Ioanna Papathanasiou, Charalampos Balis, Evanthia Mourmoura, Aspasia Tsezou
Hypertrophic chondrocyte apoptosis is an essential feature of endochondral ossification and OA progression. BAX (Bcl-2-associated X protein) is exclusively detected in OA chondrocytes (in the OA network (Figure 5)) and is connected with the mitochondrial porins VDAC1/VDAC2 in MEBlue (depleted in OA) in the glycolysis functional group. VDAC1 is a key player in mitochondrial mediated apoptosis by promoting the permeabilization of the mitochondrial outer membrane through the formation of BAX/VDAC1 hetero-oligomers possibly allowing the release of cytochrome c from the inner mitochondrial membrane to the cytosol. Depletion of VDAC1 by siRNA-mediated knock down has led to decreased activation of BAX in cisplatin treated A549 NSCLC (non-small cell lung carcinoma), AGS gastric cancer and HeLa cervix carcinoma cells [77]. In view of these observations VDAC1/VDAC2 depletion in OA chondrocytes suggests reduced BAX pro-apoptotic activity.
Uncovering the proteome response of murine neuroblastoma cells against low-dose exposure to saxitoxin
Published in Toxicology Mechanisms and Methods, 2018
Xiao Chen, Ye Sun, Haiyan Huang, Wei Liu, Panpan Hu, Xinfeng Huang, Fei Zou, Jianjun Liu
Saxitoxin is reported to inhibit voltage-dependent sodium (Pratheepa and Vasconcelos 2017), potassium (Wang et al. 2003) and calcium channels (Sun et al. 2008). In this study, the down-regulation of VDAC1 and HNRPL suggested the membrane depolarization was induced by low-dose saxitoxin exposure (10 nM for 24 h). HNRPL as splicing factors is regulated by Ca2+/calmodulin-dependent protein kinase IV (Yu et al. 2009). HNRPL also induces the membrane depolarization (Liu et al. 2014). Therefore, it is possible that the inhibition of sodium (Pratheepa and Vasconcelos 2017)/potassium (Wang et al. 2003)/calcium channels (Sun et al. 2008) by saxitoxin affected the downstream signaling pathway and altered the expression of HNRPL. VDAC1 regulates the outer mitochondrial membrane permeability. VDAC1and mitochondrial calcium uniporter co-regulate the transport of calcium in primary cerebellar granule neurons (Liao et al. 2015). Malfunction of VDAC1 increased the influx of water and calcium into the mitochondria and changed the mitochondria membrane potential. The down-regulation of the VDAC1 and HNRPL may associate with the neurotoxicity of low-dose exposure of saxitoxin. It is possible that other sodium/potassium/calcium-dependent kinase could be affected after low-dose saxitoxin intoxication. For example, expressions of other ion-regulating proteins like connexins could also be included in the future.
Combining nano-differential scanning fluorimetry and microscale thermophoresis to investigate VDAC1 interaction with small molecules
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Hubert Gorny, Angélique Mularoni, Jean-Guy Delcros, Céline Freton, Jordane Preto, Isabelle Krimm
The voltage-dependent anion channel 1 (VDAC1) is the most abundant protein of the outer mitochondrial membrane (OMM). VDAC1 is responsible of approximatively 90% of the exchanges between the mitochondrion and the cytoplasm regulating the transport of most ions and metabolites of molecular weight less than 5 kDa1–3. In addition, the channel is considered a hub protein interacting with many partners involved in the mitochondrial function including apoptosis4–6. In response to a pro-apoptotic signal, VDAC1 was shown to homo-oligomerize forming a large pore that enables the release of apoptogenic factors from the mitochondrial intermembrane space (IMS) to the cytosol5,7,8. Apoptogenic factors include the apoptosis inducing factor (AIF), Smac/DIABLO and the cytochrome C, leading to caspase activation and subsequent cell death. The above factors can also be released via large hetero-oligomers made of VDAC1 and of the pro-apoptotic protein Bax from the Bcl-2 family, resulting in the same apoptotic effects9. The pro-apoptotic activity of VDAC1 can be regulated through its interaction with anti-apoptotic partners including members of the Bcl-2 family (BcL-XL, Bcl-2)10 as well as Hexokinases I and II (HKI and HK2) that prevent the formation of large-pore oligomers involving VDAC111. Efforts are currently being made to provide insights into the structure of VDAC1 complexes including homo-7, hetero-oligomers and the HK-VDAC1 complex12,13 although no experimental structure of these complexes has yet been obtained. As a result, related mechanisms and their relationships to channel function remain largely misunderstood.