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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 Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
Two mitochondria can fuse through mergers of successive outer and inner mitochondrial membranes (mitochondrial fusion). The reverse phenomenon is the mitochondrial fission. Relatively few proteins directly involved in fusion and fission processes have been identified so far. Three GTPase proteins are known to regulate the fusion process: mitofusin 1 (MFN1), mitofusin 2 (MFN2), and optic atrophy protein 1 (OPA1). MFN1 and MFN2 are mitochondrial transmembrane proteins localized in the outer membrane and appear to play similar roles in mitochondrial fusion. OPA1 has been shown to be the mediator of inner membrane fusion102,103. Mitochondrial fission mainly involves the dynamin-related protein 1 (Drp1), also referred to as the dynamin-like protein 1 (DLP1), a member of the conserved dynamin-related large GTPase superfamily. This cytosolic protein is recruited on the external surface of the mitochondrial outer membrane by Fis1, which acts as a receptor to Drp1. Drp1 can also oligomerize and assemble into rings or spirals surrounding the mitochondrial outer membrane104. GTP hydrolysis leads to the formation of a constriction initiating mitochondrial fission. It has been shown that GDAP1 is a regulator of mitochondrial fission104,105 and that GDAP1-induced fission is dependent on fission factors Fis1 and Drp1106. Mitochondrial fusion and fission not only determine mitochondrial morphology and size, but also regulate mitochondrial distribution.
Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Mitofusin1 (Mfn1), mitofusins2 (Mfn2), and OPA1 are proteins involved in mitochondrial fusion. Abnormality of these proteins may cause abnormal mitochondrial structure and function, resulting in inefficient cellular respiration in many tissues,73–75 including the aging heart.76,77 Disruption of both Mfn1 and Mfn2 is embryonic lethal. Deletion of Mfn1 may cause mitochondrial fragmentation, which lead to cardiac hypertrophy and dysfunction.77 In the heart, deficiency of Mfn2 is associated with the disruption of cell cycle progression, cardiac hypertrophy, reduced oxidative metabolism, and altered mitochondrial permeability transition, which may cause systolic dysfunction.77 Consistent with this, downregulation of Mfn2 has been reported in several experimental models of heart failure.78 Suppression of Mfn2 and OPA1 in cardiomyocytes exhibits altered mitochondrial morphology, resulting in large pleomorphic and irregular mitochondria with disrupted cristae structure.77,79 Mitochondrial fusion is an essential mechanism to maintain mitochondrial integrity and function. Partial deletion of both Mfn1 and 2 in mice has been shown to cause mitochondrial fragmentation, impaired mitochondrial respiration, and cardiomyopathy.80 The changes in mitochondrial dynamics and their role in aging warrant further study.
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.
Enteropathogenic Escherichia coli regulates host-cell mitochondrial morphology
Published in Gut Microbes, 2022
Jennifer Lising Roxas, Shylaja Ramamurthy, Katie Cocchi, Ilga Rutins, Anusha Harishankar, Al Agellon, John Scott Wilbur, Gresa Sylejmani, Gayatri Vedantam, V.K. Viswanathan
Mitochondrial shape, function and positioning are dynamically regulated in eukaryotic cells.12 The processes of fusion, fission and mitophagy regulate mitochondrial shape in response to cellular cues, including stress. Fission facilitates organelle distribution during mitosis. It also serves to demarcate and dispose of damaged mitochondria via mitophagy wherein defective organelles are enclosed in a double membrane, and eliminated via a lysosome-dependent pathway.13 On the other hand, mitochondrial fusion alleviates cellular stress by combining the contents of partially damaged organelles.13 Overall, impaired fusion promotes mitochondrial fragmentation (which is correlated with lower respiratory activity), while inhibition of fission leads to fusion of adjacent mitochondria resulting in fused networks that have increased numbers of cristae, and that are optimal for ATP synthesis.14
Effect of mycobacterial proteins that target mitochondria on the alveolar macrophages activation during Mycobacterium tuberculosis infection
Published in Experimental Lung Research, 2022
Iris Selene Paredes-González, Omar Emiliano Aparicio-Trejo, Octavio Ramos-Espinosa, Manuel Othoniel López-Torres, Milena Maya-Hoyos, Monserrat Mendoza-Trujillo, Alejandra Barrera-Rosales, Dulce Mata-Espinosa, Juan Carlos León-Contreras, José Pedraza-Chaverri, Clara Espitia, Rogelio Hernández-Pando
Mitochondria are involved in catabolic and anabolic reactions and are critical for respiratory ATP production. Interestingly, the organelle’s morphology is directly related to their function. The fusion and fission processes constantly modify the mitochondrial network. Fission exscinds a mitochondrial tubule into two, while fusion connects two tubules to form a longer one.15,16 Cycles of mitochondrial fusion and fission are essential for maintaining mitochondrial activity, influenced by metabolic and cellular signals, depending on the cell type and organism.17,18 Interconnected (fused) mitochondria are frequently present in cells with active mitochondrial respiration, while metabolically quiescent cells are characterized by presenting small fragmented (fission) mitochondria.19,20 Thus, part of the mitochondrial morphology can be represented by changes in cellular respiration.21