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Regulation of Antiviral Immunity by Mitochondrial Dynamics
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Mohsin Khan, Hasan Imam, Saiful Anam Mir
In mammalian cells, the central player of mitochondrial fission, Drp1 is primarily localized in the cytosol and the accessory proteins, MiD (mitochondrial dynamics protein) and Mff (mitochondrial fission factor) mediates its recruitments to the mitochondria by acting as ligands for Drp1 (Chang and Blackstone, 2007; James et al., 2003; Loson et al., 2013). Although it’s not clear about the exact mechanism of mitochondrial fission but recent evidence indicates that endoplasmic reticulum (ER) tubules are the key players in this event (Friedman et al., 2011). ER tubules can wrap around and constrict the mitochondria to mark them for subsequent scission by Drp1 (Friedman et al., 2011). Since ER-mitochondrial contact sites are enriched with Drp1, it is assumed that ER-mitochondria connection directs mitochondrial fragmentation (Friedman et al., 2011; Lee and Yoon, 2014). In addition, the cells depleted for Drp1 and Mff still showed mitochondrial constriction at ER contact sites which indicates that ER-mediated flagging of mitochondrial fission sites occurs before the mitochondrial recruitment of Drp1 (Friedman et al., 2011). ER-mediated constriction of mitochondrial tubules requires mechanical force and it seems to be generated by actin assembly via interaction with ER-associated INF2 (Inverted Formin 2) at the ER-mitochondrial contact site (Korobova et al., 2013). Fission1 (Fis1) protein was the first molecule identified as Drp1 receptor in yeast, which has a C-tail protein anchored on OMM and displays uniform distribution (Cerveny and Jensen, 2003; Gomes and Scorrano, 2008; Lee et al., 2004). Another C-tail anchored protein on OMM is Mff, which is a receptor of Drp1 and interacts transiently through its N-terminal cytoplasmic domain. It colocalizes mainly with Drp1 foci on the OMM (Gandre-Babbe and van der Bliek, 2008; Loson et al., 2013). Mff knockdown results in mitochondrial elongation but its overexpression stimulates mitochondrial recruitment of Drp1 and mitochondrial fragmentation (Gandre-Babbe and van der Bliek, 2008; Otera et al., 2010). In the absence of Fis1 and Mff, the MiDs can mediate mitochondrial fission (Loson et al., 2013). Silencing any of these genes results in increased mitochondrial length and interconnectivity, that indicates that these proteins can positively regulate mitochondrial fission. Interestingly, overexpression of MiDs also results in elongated mitochondria, which is associated with increased phosphorylation of Drp1 at S637 site and for this reason Drp1 function is negatively regulated (Chang and Blackstone, 2007). When cells were mutated for Drp1, they become resistant to mitochondrial fragmentation induced by depolarization but they also exhibit substantial mitochondrial fragmentation when treated with apoptotic stimuli such as actinomycin D and etoposide. These observations prove that mitochondrial fission can also occur through Drp1 independent mechanisms. In support of this, it was observed that pore-forming toxin listeriolysin O, secreted by Listeria monocytogens, can induce mitochondrial fragmentation which is dependent on actin cytoskeleton but independent of traditional fission protein Drp1 (Stavru et al., 2013).
The protective effect of tanshinone IIa on endothelial cells: a generalist among clinical therapeutics
Published in Expert Review of Clinical Pharmacology, 2021
Jun Feng, Lina Liu, Fangfang Yao, Daixing Zhou, Yang He, Junshuai Wang
Epidermal cells, pre-treated with TSA, exhibited enhanced resistance to hypoxia by activating Wnt signaling and up-regulating stem cell-related biomarkers [93,104]. TSA attenuated hypoxia-induced oxidative stress to increase cell survival from hypoxia by regulating the expression of AP-1 subunits through MAPK and Nrf2 transcription factor, which in turn contributed to the maintenance of higher levels of antioxidant enzymes and genes [105]. TSA supplementation reduced inverted formin-2 expression, sustained mitochondrial metabolism, and attenuated mitochondrial apoptosis, favoring HaCaT cell (human keratinocytes cell) survival in an oxidative injury microenvironment [106]. TSA pre-treatment protected human lens epithelial cell cells against H2O2-induced injury [107]. In general, treatment with TSA can effectively reduce cellular oxidative stress to ameliorated mitochondrial dysfunction and fission and endothelial dysfunction.
Inhibitory effect of Tanshinone IIA on inverted formin-2 protects HaCaT cells against oxidative injury via regulating mitochondrial stress
Published in Journal of Receptors and Signal Transduction, 2019
Zhiyin Xie, Yu Zhou, Xingwu Duan, Lirong Yang
Recently, the mitochondrial function has been found to be regulated by inverted formin-2 (INF2), a novel mitochondrial dynamic regulator [5]. Increased INF2 promotes mitochondrial fission with the help of F-actin. Activated mitochondrial fission has been acknowledged as a hall-marker of cell death. For example, in cardiac ischemia–reperfusion injury, INF2 is upregulated at the stage of reperfusion and increased INF2 promotes the mitochondrial apoptosis in cardiomyocyte [7]. Besides, INF2 is also linked to the viability of prostate cancer in a manner dependent on mitochondrial stress [8]. The pro-apoptotic effect of INF2 has also been verified in brain ischemic injury and this process is primarily modulated by mitochondrial stress [9]. Interestingly, in addition to mitochondrial damage, INF2 is also connected with ER stress which has been considered as an upstream event of mitochondrial calcium overloading [10]. Therefore, the above information inform us that INF2 seems to be a primary mediator of mitochondrial dysfunction in epidermal cells. However, this concept has not been tested now.
A Novel Nonsense FMN2 Mutation in Nonsyndromic Autosomal Recessive Intellectual Disability Syndrome
Published in Fetal and Pediatric Pathology, 2021
Orhan Gorukmez, Ozlem Gorukmez, Arzu Ekici
Mental developmental disorders are highly heterogeneous in terms of clinical and genetic aspects. FMN2 (Formin 2) is a gene that has recently been reported to cause syndromic. Nonsyndromic Autosomal-Recessive Intellectual Disability Syndrome (MRT47, MIM: 616193) is caused by mutations in both alleles of FMN2 gene [1–5]. In this article, clinical findings of different types of FMN2 gene mutations are presented and compared in our case diagnosed with intellectual disability (ID).