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Mitochondrial Dysfunction and Oxidative Stress in the Pathogenesis of Metabolic Syndrome
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
The ER-mitochondria interfaces are enriched in protein enzymes that participate in the synthesis and transport of phospholipids and glycosphingolipids122,130, such as phosphatidylserine (PS) synthase 1 and 2 that are involved in phospholipid (PL) synthesis. Newly synthesized PS is preferentially transferred from ER to mitochondria123, where it is used for the synthesis of PE127. In mammals, PE is also transferred back to the ER for its conversion to PC via PE methylation by the hepatic enzyme PE-N-methyltransferase131. Other lipid biosynthetic enzymes such as glycerol 3-phosphate acyltransferase, acylcoA synthase 4, diacylglycerol acyltransferase 2 and the microsomal triacylglycerol transfer protein are also localized at MAMs, which are considered structural components of the MAMs, contributing both to the stability and dynamics of this structure127,132. Another well-known protein complex identified at MAM contact site is the Ca2+ channeling complex made of the inositol 1,4,5-trisphosphate receptor (IP3R) at the ER, the cytosolic chaperone glucose-regulated-protein 75 (GRP75) and the the mitochondrial porin voltage-dependent anion channel (VDAC) at the outer mitochondrial membrane (OMM) for mediating the transfer of Ca2+ from ER to mitochondria133. Once Ca2+ ions have passed through the OMM, they enter into the matrix through a mitochondrial Ca2+ uniporter (MCU). Recently, another mitochondrial matrix protein, cyclophilin D (CYPD), was found to interact with and regulate this Ca2+ channeling complex. CYPD belongs to the family of the peptidyl-prolyl cis-trans isomerases and regulates the opening of the mitochondrial permeability transition pore in stress conditions, particularly during myocardial ischemia-reperfusion injury134. At the MAM interface, CYPD forms a high molecular complex with the IP3R-Grp75-VDAC complex in both cardiomyocytes and hepatocytes and regulated Ca2+ exchange between these two organelles135–137.
Novel Intriguing Strategies Attenuating to Sarcopenia
Published in Chad Cox, Clinical Nutrition and Aging, 2017
Kunihiro Sakuma, Akihiko Yamaguchi
Ca2+ overload is known to cause cellular necrosis by directly inducing the opening of the mitochondrial permeability transition (MPT) pore [96, 97]. The MPT pore spans the inner and outer membranes of the mitochondria and, when opened for prolonged periods of time, leads to loss of ATP generation, swelling, rupture, and induction of cell death [96, 97]. Cyclophilin D is a mitochondrial matrix prolyl cis-trans isomerase that directly regulates calcium—and reactive oxygen species-dependent MPT and cellular necrosis. Indeed, mice lacking Ppif (the gene-encoding cyclophilin D) show protection from necrotic cell death in the brain and heart after ischemic injury, and mitochondria isolated from these mice are resistant to calcium-induced swelling [98, 99]. Additionally, genetic deletion of Ppif attenuated various dystrophic symptoms (fiber atrophy, fiber loss, invasion by inflammatory cells, and swollen mitochondria) of mice lacking δ-sarcoglycan and the α2-chain of laminin-2 [100]. Millay et al. [100] demonstrated that the subcutaneous injection of Debio-025, a potent inhibitor of the cyclophilin family, improved calcium overload-induced swelling of mitochondria and reduced manifestations of necrotic disease such as fibrosis and central nuclei, in mdx mice, a model of DMD. In addition, treatment with Debio-025 prevented mitochondrial dysfunction and normalized the apoptotic rates and ultrastructural lesions of myopathic Col6a1−/− mice, a model of human Ullrich congenital muscular dystrophy and Bethlem myopathy [101]. More recently, orally administered Debio-025 reduced creatine kinase blood levels and improved grip strength in mdx mice after 6 weeks of treatment [102]. This effect on muscular dystrophy was greater than that of prednisone, currently the standard for treatment of DMD [103, 104]. However, it had not been examined until now whether Debio-025 also has a therapeutic effect on the loss and/or atrophy of muscle fiber with aging in rodents as well as humans. Since there are many symptoms in common between muscular dystrophy and sarcopenia, treatment with Debio-025 may counteract sarcopenic symptoms.
Novel drug discovery strategies for atherosclerosis that target necrosis and necroptosis
Published in Expert Opinion on Drug Discovery, 2018
Isabelle Coornaert, Sam Hofmans, Lars Devisscher, Koen Augustyns, Pieter Van Der Veken, Guido R.Y. De Meyer, Wim Martinet
Inhibition of MPT can also be a therapeutic strategy to treat atherosclerosis. Cyclosporin A, a widely used immune suppressant for the treatment of several autoimmune disorders, binds to cyclophilin D, which is a regulator of the MPT pore. Inhibition of cyclophilin D by cyclosporin A blocks MPT and, in turn, necrosis. Importantly, cyclosporin A treatment stimulates hyperlipidemia and atherosclerosis [46]. Therefore, cyclosporin A is not suitable to use for the treatment of atherosclerosis.
The development and hepatotoxicity of acetaminophen: reviewing over a century of progress
Published in Drug Metabolism Reviews, 2020
Mitchell R. McGill, Jack A. Hinson
The mitochondrial permeability transition (MPT) may be a particularly important mechanism in APAP toxicity (Kon et al. 2004; Masubuchi et al. 2005; Reid et al. 2005) (Figure 6). The MPT occurs with depolarization of the inner mitochondrial membrane, uncoupling of oxidative phosphorylation, release of intra-mitochondrial ions and metabolic intermediates, mitochondrial swelling, and decreased ATP synthesis. Blockade of APAP toxicity both in vitro and in vivo by MPT inhibitors has been reported. Kon et al. (2004, 2007) showed that APAP toxicity in cultured mouse hepatocytes was inhibited by cyclosporine A and by the non-immunosuppressive cyclosporine A analog NM811. Cyclosporine A did not alter APAP-induced GSH depletion, which suggests that the prevention of toxicity did not occur by inhibition of metabolism of APAP to NAPQI. Reid et al. (2005) examined the effect of MPT inhibitors in freshly isolated mouse hepatocytes using the approach of Boobis (Boobis et al. 1986; Tee et al. 1986). In these studies, APAP toxicity was inhibited by the MPT inhibitors cyclosporine A, trifluoperazine, or dithiothreitol. Subsequently, Banerjee et al. (2017) examined APAP toxicity and the effect of trifluoperazine in freshly isolated hepatocytes in greater detail. They reported that toxicity occurs with increased NO and superoxide formation, increased protein nitration, loss of mitochondrial membrane potential, decreased ATP levels, decreased oxygen consumption rate, and decreased NADH levels. All of these parameters were reversed in the presence of trifluoperazine without altering GSH depletion or APAP protein adduct formation. Finally, Ramachandran et al. (2011) reported that mice deficient for cyclophilin D (CypD), thought by some to be a component of the MPT pore, are less susceptible to APAP hepatotoxicity than wildtype mice. Together, these data have been interpreted as demonstrating that the MPT is a critical step in APAP hepatotoxicity, though the exact composition of the MPT pore and the role of CypD in it remain highly controversial (Baines and Gutiérrez-Aguilar 2018).
HSP60 in cancer: a promising biomarker for diagnosis and a potentially useful target for treatment
Published in Journal of Drug Targeting, 2022
Bo Sun, Ganghui Li, Qing Yu, Dongchun Liu, Xing Tang
Mitochondrial HSP60 can directly interact with apoptosis-related factors in the mitochondria and inhibit the activation of mitochondrial apoptotic pathways. The specific anti-apoptotic mechanisms are shown in Figure 1, and are as follows. (1) Inhibit the p53-Bax pathway: the P53-dependent apoptotic pathway is a crucial apoptotic pathway in normal cells and is usually inactivated in tumours. This is because HSP60 can bind to p53, and reduce Bax expression to prevent the activation of p53-dependent apoptotic signalling pathways [41]. (2) Maintain Cyclophilin D (CypD) stability: CypD is a component of mitochondrial permeability transition pores. The permeability of the mitochondria is very important for energy supply in tumour cells [42]. HSP60 can form a multimeric complex with HSP90, tumour necrosis factor receptor-related protein-1 (TNFR-related protein-1) and CypD to maintain the permeability of the mitochondria and play an anti-apoptotic role [42]. (3) Promote Bcl-2 and Bcl-xl protein: An adenovirus vector is used to transduce HSP60 genes into cardiomyocytes to overexpress HSP60. HSP60 overexpression inhibits doxorubicin-induced cardiomyocyte apoptosis by increasing the abundance of Bcl-2 and Bcl-xl protein, while reducing Bax content [43]. (4) Maintain survivin cytoprotection: HSP60 can maintain the stability of survivin, an anti-apoptotic protein, to protect cell survival [41,42]. (5) Stabilised by Lon protease: Lon is a mitochondrial matrix protein, which is overexpressed in tumour cells. Lon can combine with the HSP60-mtHSP70 complex to protect HSP60 from oxidative stress [44]. HSP60 degradation can activate the p53-dependent apoptotic pathway; however, the stable HSP60-mtHSP70 complex can prevent this process [44]. (6) Neutralise β-amyloid disruption: It has been demonstrated that the modified adenovirus vector can transfect the Aβ-(1–42) gene into human neuroblastoma cells SH-SY5Y. Aβ-(1–42) accumulation in SH-SY5Y cells can damage the activity of mitochondrial electron transport chain complex IV, causing an increase in intracellular ROS and a decrease in ATP, leading to apoptosis. However, HSP60 can protect the integrity of the mitochondrial respiratory chain by protecting the stability of complex IV to inhibit neuronal apoptosis [45].