China
Africa
Explore chapters and articles related to this topic
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).
Loss of mDia1 and Fhod1 impacts platelet formation but not platelet function
Published in Platelets, 2021
Malou Zuidscherwoude, Elizabeth J. Haining, Victoria A. Simms, Stephanie Watson, Beata Grygielska, Alex T. Hardy, Andrea Bacon, Stephen P. Watson, Steven G. Thomas
Further evidence to support this notion can be found by looking in more detail at the molecular function of the two remaining proteins, Daam1 and Inf2. Daam1 is released from its auto-inhibited state by the combined actions of Disheveled (Dvl) and RhoA [50]. RhoA is activated upon platelet stimulation (reviewed by [51]), and work by Steele et al. demonstrated that upon platelet activation Dvl associated with Daam1. Therefore, it is highly likely that Damm1 would be contributing to actin polymerization in activated platelets. To the best of our knowledge, Inf2 has not been studied in platelets and so the contribution of this formin to platelet organization is unclear. However, biochemical studies on Inf2 indicate that it contains a WH2 domain which is involved in mediating its auto-inhibition [52] and that it is binding of actin monomers to this domain that relieves the auto-inhibition [53]. The initial increase in actin filament severing and depolymerization immediately upon platelet activation could therefore provide an environment for the activation of Inf2 and subsequent nucleation/elongation of new actin filaments. A further intriguing possibility is the observation that Inf2 can regulate the activity of mDia1 [54,55] and that this might be important for modulating the interaction of mDia1 with microtubules [56]. The implications of this for platelets remain unclear, especially in the absence of mDia1 and Fhod1, but it would be interesting to study the role of Inf2 and Daam1 in platelet function further.
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.
Formin proteins in megakaryocytes and platelets: regulation of actin and microtubule dynamics
Published in Platelets, 2019
Malou Zuidscherwoude, Hannah L.H. Green, Steven G. Thomas
Differences also exist in the activity and functions of individual formins in cells. In comparison with mDia1, FHOD1 is less effective at processively elongating actin filaments, but rather acts as an actin bundling factor while protecting filaments from depolymerisation (17,18). INF2 has a Wiskott–Aldrich syndrome homology region 2 (WH2) domain which replaces the DAD found in the DRFs and is able to bind monomeric actin. Interestingly, INF2 is able to sever filaments and accelerate actin filament depolymerisation on the pointed end by virtue of its WH2 domain, as well as to nucleate and elongate actin via its FH2 domain. The switch between polymerisation and depolymerisation activity is thought to be mediated by the hydrolysis of bound ATP within actin subunits upon addition to a filament and the subsequent release of phosphate (19,20).