Burkholderia
Dongyou Liu in Laboratory Models for Foodborne Infections, 2017
With respect to a mechanism of action, BA inhibits oxidative phosphorylation by binding to the adenine nucleotide translocator, which normally shuttles ADP and ATP across the inner mitochondrial membrane.168 The activity of this transporter is thought to inhibit cellular apoptosis.169 Because BA inhibits oxidative phosphorylation, the only way for cells to generate ATP is through anaerobic glycolysis.170 This metabolic changeover is responsible for the symptoms of intoxication. Glycogen stores are broken down to allow for an increased level of glycolysis, leading to hyperglycemia and increased lactic acid levels, but these stores are soon depleted, resulting in hypoglycemia and an inability to regenerate ATP.171 It is the ATP depletion that is fatal and not the hypoglycemia, as the injection of glucose is insufficient to prevent death.171
Mitochondrial Dysfunction in Huntington Disease
Abhai Kumar, Debasis Bagchi in Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
The mPTP is a nonspecific channel whose activation is associated with mitochondrial defects and has been demonstrated to be involved in several HD models (Wong and Cuervo 2010; Gottlieb and Carreira 2010; Komatsu et al. 2006; Banerjee, Beal, and Thomas 2010; Yang et al. 2005; Webb et al. 2003; Tian et al. 2012). This is a structure on the mitochondrial membrane that mainly consists of three proteins—cyclophylin D (CypD) located in the mitochondrial matrix, voltage-dependent anion channel (VDAC) found in the outer mitochondria membrane, and adenine nucleotide translocator located in the mitochondrial inner membrane; and their dysregulated interaction participate in neurodegeneration (Liu et al. 2009; Chu et al. 2009; Yang et al. 2006). Mutant HTT increases sensitivity to calcium-induced mPTP opening of mitochondria resulting in apoptotic cell death of neurons (Jin and Johnson 2010). In vitro and in vivo studies have demonstrated that mitochondria isolated from striatal neurons of HD mice have reduced calcium uptake capacity and enhanced sensitivity to calcium-induced mitochondrial membrane depolarization, which is associated with increased sensitivity of the mPTP (Fernandes et al. 2007; Milakovic, Quintanilla, and Johnson 2006; Lim et al. 2008). The mPTP is highly sensitive to the changes in intracellular calcium levels as well as oxidative stress (Tian et al. 2012) and contributes to mitochondrial permeability, matrix swelling, and uncoupling of the oxidative phosphorylation that leads to deficits of respiration (Battisti et al. 2008).
Di-Calciphor-Dependent Protection Against Cell Death Due to Mitochondrial Failure
John J. Lemasters, Constance Oliver in Cell Biology of Trauma, 2020
Several years ago we obtained evidence for a control mechanism that functions to prevent irreversible damage to mitochondria during short-term anoxia7,8 (see Figure 1). This mechanism involves a co-ordinated inhibition of ion transport systems in the mitochondrial inner membrane;9 activation of this mechanism delays collapse of the electrochemical ion gradients across the inner membrane.8 The specific ion transport systems affected are those whose continued function would rapidly collapse the membrane potential. These include the ATP synthase, adenine nucleotide translocator, phosphate transporter, Ca2+ uniporter, and glu/asp transport system.10,11 Rapid and efficient inhibition of these systems slows the electrophoretic and pH-dependent movement of ions across the membrane, prevents osmotic swelling and preserves the ability of mitochondria to recover upon re-oxygenation.
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
As shown in Figure 1(b), cancer cells promote the first irreversible step of glycolysis by accelerating glucose uptake, as well as upregulating hexokinases (HKs) including HK1 and HK2. The facilitation of this critical step subtly prevents glucose from escaping from the cell through glucose transporters. Most notably, HK2, which binds to the outer membrane of mitochondria, plays a crucial role in cancer cells by cooperating with four pivotal partners including plasma membrane glucose transporter (Glut), the mitochondrial voltage-dependent anion channel (VDAC), the ATP synthase located in the inner mitochondrial membrane and the adenine nucleotide translocator that transports the ATP to the VDAC-HK2 complex [5]. In addition to these delicate collaborations that greatly facilitate glycolysis and subsequent biosynthesis, HK2 is essential to help cancer cells evade mitochondrial-induced apoptosis by binding to VDAC [6].
Protective effects and mechanism of action of ruscogenin in a mouse model of ovalbumin-induced asthma
Published in Journal of Asthma, 2022
Shanshan Zhan, Wei Wang, Lingfei Kong
Oxidative stress is generated when the free radical content exceeds the antioxidant capability. Free radicals are generally either reactive nitrogen radicals or ROS such as hydroxyl radicals, superoxide radical anions, and hydrogen peroxide (25). Mitochondria are the primary source of cellular ROS. The cross-linking of ROS with specific sulfhydryl groups results in stabilization of the cytoplasmic, or “c” conformation of the adenine nucleotide translocator, which interacts with VDAC to regulate downstream apoptotic signals (26). In MAM, VDAC1 directly interacts with molecules such as IP3R and GRP75, resulting in the release of calcium from the ER (27). When VDAC1 exists in an open state, the calcium ion levels are maintained by the mitochondrial calcium uniporter (MCU) and Na+/H+/Ca2+/NA+ reverse transporters. When compounds targeting VDAC1 alter the conformation of VDAC1 (resulting in a closed conformation), the calcium level in the intermembrane space increases, resulting in activation of the MCU and overloading of the mitochondria (28). An enhanced mitochondrial calcium level results in alteration of the mitochondrial membrane potential, thereby triggering the opening of the mitochondrial permeability transition pore, which in turn stimulates the release of cytochrome C into the cytoplasm, ultimately resulting in apoptosis (29).
Lucialdehyde B suppresses proliferation and induces mitochondria-dependent apoptosis in nasopharyngeal carcinoma CNE2 cells
Published in Pharmaceutical Biology, 2023
Lingxue Liu, Zhangning Yu, Jing Chen, Benchen Liu, Changhui Wu, Ye Li, Jianhua Xu, Peng Li
ROS mainly originate from the mitochondria and the mitochondria are the main site of ROS-induced damage (Farías et al. 2017). The presence of a large number of ROS oxidizes the thiol group of adenine nucleotide translocase (ANT) and causes the excessive opening of mPTP, which leads to an increase in the permeability of the mitochondrial membrane and a decrease in MMP (Boyman et al. 2019). As a multifunctional second messenger, Ca2+ plays an essential role in the production of ROS (Sabharwal and Schumacker 2014). The excessive accumulation of mitochondrial Ca2+ may also trigger mPTP opening, thereby decreasing the MMP (Wang et al. 2019). As cell-death inducers, Ca2+ and ROS can activate the mitochondrial pathway (Dong et al. 2017). The results of the present study showed that LB significantly increased the ROS level and Ca2+ content in CNE2 cells, suggesting that LB activated the mitochondrial pathway to induce CNE2 cells apoptosis through the accumulation of ROS and calcium.
Related Knowledge Centers
- Cytoplasm
- Inner Mitochondrial Membrane
- Oxidative Phosphorylation
- Mitochondrial Matrix
- Adenosine Triphosphate
- Mitochondrial Carrier
- Adp/Atp Translocase 1
- Adp/Atp Translocase 2
- Adp/Atp Translocase 3
- Adp/Atp Translocase 4