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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
Initially discovered in yeast, human homologues to the main components of both mitochondrial fission and fusion machinery have been identified along with their underlying mechanisms of action. In eukaryotes, mitochondrial fission is regulated by the proteins dynamin-related protein (DRP1), mitochondrial fission 1 protein (FIS1), mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 (MiD49) and 51 kDa (MiD51). Mitochondrial fusion is primarily regulated by the proteins mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) (51). Fission involves the recruitment of the GTPase enzyme DRP1 from the cytosol to the OMM by MFF, FIS1, MiD49, and MiD51 (82). This recruitment stimulates DRP1 to form a helical assembly along the surface of the mitochondria and begins with constriction and culminates with the ultimate division of the mitochondria into two smaller, functional mitochondria (39). Research has also identified that the ER may have direct involvement in initiating fission by extending tubules which constrict the mitochondria prior to the recruitment of DRP1 (38). These ER tubules are extensions of the ER which wrap around neighbouring mitochondria and initiate a fission event.
Mitochondrial Dysfunction Linking Obesity and Asthma
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Naveen K. Bhatraju, Anurag Agrawal
Inside a cell, mitochondria are highly dynamic, motile and exhibit variable morphologies coupled to their functional state. A balance between the fission and fusion processes regulates the spatiotemporal organization of mitochondria into either reticular networks of elongated mitochondria or short fragments dispersed throughout the cytoplasm. Mitochondrial fusion/fission is a tightly regulated process involving a coordinated interplay of a number of proteins. The main proteins involved in the regulation of mammalian mitochondrial fusion are mitofusin 1 and 2 (Mfn1 and 2) and autosomal dominant optic atrophy-1 (Opa1). Mitofusins and Opa1 are respectively localized in the outer and the inner mitochondrial membrane controlling the outer and inner membrane fusions. Additional roles for both Mfn2 and Opa1 have also been reported. While Opa1 plays a role in cristae remodelling, Mfn2 has been shown to be implicated in the structural and functional connection between mitochondria and endoplasmic reticulum (ER) (Theurey & Rieusset 2017). On the other hand, mitochondrial fission is regulated by dynamin related protein 1 (Drp1) and fission protein 1 (Fis1). Fis1 is an outer mitochondrial membrane protein that helps in the recruitment of Drp1, a cytosolic protein, during mitochondrial fragmentation (Nunnari & Suomalainen 2012). Mitochondrial fission factor (Mff) is another protein localized in the outer mitochondrial membrane that has been shown to have similar function to that of Fis1. The reasons for such high dynamicity of mitochondrial structure are currently unclear. Perhaps, reducing mtDNA heterogeneity through matrix content mixing via mitochondrial fusion may connect the mitochondrial dynamics to the maintenance of mitochondrial health (Chen et al. 2010). Further, mitochondrial fission has been shown to be critical to cellular adaptation to stress and thus cell survival. The strategic positioning of mitochondria in the metabolic flux allows it to sense and adapt to alterations in nutrient availability (Naviaux 2014). Mitochondrial capacity to switch between the fatty acid and glucose oxidation during fasting and fed states forms the core of the metabolic flexibility concept (Smith et al. 2018). Metabolic flexibility is defined as the remarkable ability of a cell/organ/organism to tune metabolism to maintain the energy homeostasis depending on the substrate availability and environmental demand. Mitochondrial response to altered energy demands involve both acute changes such as changes in mitochondrial dynamics and post-translational modifications associated with prompt activity modulation, and long term transcriptional responses such as changes in mitochondrial biogenesis and mitophagy that regulate mitochondrial volume and density (Gao et al. 2014; Smith et al. 2018). However, dysregulation of either of these adaptive responses has been shown to result in metabolic inflexibility, a key pathology associated with a number of metabolic disorders such as insulin resistance, type-II diabetes and metabolic syndrome.
Impact of UCP2 depletion on heat stroke-induced mitochondrial function in human umbilical vein endothelial cells
Published in International Journal of Hyperthermia, 2022
Wei Huang, Liangfeng Mao, Weidang Xie, Sumin Cai, Qiaobing Huang, Yanan Liu, Zhongqing Chen
Mitochondria are essential organelles in mammalian cells, and play a central role in metabolism, cell death, and cellular senescence. Mitochondrial dysfunction, in the form of permeabilization of the inner and/or outer membranes of organelles, can eventually lead to cell apoptosis or necrosis [5,6]. Growing evidence suggests that mitochondrial dysfunction induces the loss of cellular homeostasis, which contributes to cell death during HS [7–9]. Mitochondrial function rests on the complex molecular machinery of mitochondrial dynamics-processes of fission and fusion [10]. A precise balance in mitochondrial dynamics is closely related to the maintenance of mitochondrial functions and responses to external stress [11]. Mitochondrial fission is driven by fission regulators, including mitochondrial fission factor (Mff), dynamin-related protein 1 (Drp1), and fission 1 (Fis1) [12]. In particular, the phosphorylation of Drp1 regulates its translocation to the mitochondrial membrane to induce mitochondrial fission [13,14]. Mitochondrial fusion is mediated by Mitofusin 1/2 (Mfn1/2) and optic atrophy 1 (OPA1) anchor proteins that maintain the fusion of the mitochondrial outer and inner membranes [15]. Therefore, researching the mechanism of mitochondrial homeostasis may provide an important breakthrough in HS therapy.
Inhalation of PM2.5 from diesel exhaust promote impairment of mitochondrial bioenergetics and dysregulate mitochondrial quality in rat heart: implications in isoproterenol-induced myocardial infarction model
Published in Inhalation Toxicology, 2022
Bhavana Sivakumar, Gino A. Kurian
Mitophagy, the critical event in maintaining the mitochondrial health was assessed by measuring the gene expressions of PINK, PARKIN, and OPTN (Figure 8(e,f,g)). Except in OPTN gene, the expression of PINK and PARKIN genes were downregulated in all the three experimental groups from the control, where OPTN was insignificantly decreased in the DPM + ISO group from the control. Next, we analyzed the expression pattern of genes involved in mitochondrial fission (mitochondrial fission factor [MFF], DNM1, and FIS1) and fusion (MFN1 and MFN2) (Figure 8(h,i)). Among the fusion genes, both MFN1 and MFN2 were significantly declined in all experimental groups while MFN2 alone showed an insignificant decline. On the other hand, fission genes were showed a significant decline only in DPM + ISO group from the control.
Gut bacteria signaling to mitochondria in intestinal inflammation and cancer
Published in Gut Microbes, 2020
Dakota N. Jackson, Arianne L. Theiss
Mitochondrial fission is the process by which mitochondria divide into smaller daughter mitochondria.1 Mitochondrial fission is essential to generate adequate numbers of mitochondria for growing cells and is mediated by Dynamin-Related Protein1 (Drp1), Fission 1 (Fis1), Mitochondria Fission Factor (Mff), Mitochondrial Dynamics Protein (MID49) and MID51. The OMM protein Mff recruits Drp1 from the cytosol13 to the OMM of mitochondria where it assembles into oligomeric complexes that compress the mitochondrial tubule to mediate fission.11 This action leads to OMM constriction and cleavage.11 Fis1 is located on the OMM as the receptor protein for Drp1 during its translocation from the cytosol.14 The interaction of Drp1 with Fis1 can lead to the release of cytochrome c which can induce apoptosis.11 MID49/51 are also found on the OMM and facilitate randomized screening of uncharacterized proteins whose expression cause changes in mitochondrial morphology.13