Mitochondrial Fusion Suppresses Tau Pathology-Induced Neurodegeneration and Cognitive Decline

2021 ◽  
pp. 1-13
Author(s):  
Luwen Wang ◽  
Mengyu Liu ◽  
Ju Gao ◽  
Amber M. Smith ◽  
Hisashi Fujioka ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Loss ◽  
Mitochondrial Fusion ◽  
Barnes Maze ◽  
Mitochondrial Fragmentation ◽  
Tau Pathology ◽  
Marked Suppression

Background: Abnormalities of mitochondrial fission and fusion, dynamic processes known to be essential for various aspects of mitochondrial function, have repeatedly been reported to be altered in Alzheimer’s disease (AD). Neurofibrillary tangles are known as a hallmark feature of AD and are commonly considered a likely cause of neurodegeneration in this devastating disease. Objective: To understand the pathological role of mitochondrial dynamics in the context of tauopathy. Methods: The widely used P301S transgenic mice of tauopathy (P301S mice) were crossed with transgenic TMFN mice with the forced expression of Mfn2 specifically in neurons to obtain double transgenic P301S/TMFN mice. Brain tissues from 11-month-old non-transgenic (NTG), TMFN, P301S, and P301S/TMFN mice were analyzed by electron microscopy, confocal microscopy, immunoblot, histological staining, and immunostaining for mitochondria, tau pathology, and tau pathology-induced neurodegeneration and gliosis. The cognitive function was assessed by the Barnes maze. Results: P301S mice exhibited mitochondrial fragmentation and a consistent decrease in Mfn2 compared to age-matched NTG mice. When P301S mice were crossed with TMFN mice (P301S/TMFN mice), neuronal loss, as well as mitochondria fragmentation were significantly attenuated. Greatly alleviated tau hyperphosphorylation, filamentous aggregates, and thioflavin-S positive tangles were also noted in P301S/TMFN mice. Furthermore, P301S/TMFN mice showed marked suppression of neuroinflammation and improved cognitive performance in contrast to P301S mice. Conclusion: These in vivo findings suggest that promoted mitochondrial fusion suppresses toxic tau accumulation and associated neurodegeneration, which may protect against the progression of AD and related tauopathies.

scholarly journals Non-alcoholic fatty liver disease in mice with hepatocyte-specific deletion of mitochondrial fission factor

Diabetologia ◽  
2021 ◽  
Author(s):  
Yukina Takeichi ◽  
Takashi Miyazawa ◽  
Shohei Sakamoto ◽  
Yuki Hanada ◽  
Lixiang Wang ◽  
...  
Keyword(s):  
Er Stress ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Primary Hepatocytes ◽  
Alcoholic Fatty Liver ◽  
Expression Of Genes ◽  
Specific Deletion

Abstract Aims/hypothesis Mitochondria are highly dynamic organelles continuously undergoing fission and fusion, referred to as mitochondrial dynamics, to adapt to nutritional demands. Evidence suggests that impaired mitochondrial dynamics leads to metabolic abnormalities such as non-alcoholic steatohepatitis (NASH) phenotypes. However, how mitochondrial dynamics are involved in the development of NASH is poorly understood. This study aimed to elucidate the role of mitochondrial fission factor (MFF) in the development of NASH. Methods We created mice with hepatocyte-specific deletion of MFF (MffLiKO). MffLiKO mice fed normal chow diet (NCD) or high-fat diet (HFD) were evaluated for metabolic variables and their livers were examined by histological analysis. To elucidate the mechanism of development of NASH, we examined the expression of genes related to endoplasmic reticulum (ER) stress and lipid metabolism, and the secretion of triacylglycerol (TG) using the liver and primary hepatocytes isolated from MffLiKO and control mice. Results MffLiKO mice showed aberrant mitochondrial morphologies with no obvious NASH phenotypes during NCD, while they developed full-blown NASH phenotypes in response to HFD. Expression of genes related to ER stress was markedly upregulated in the liver from MffLiKO mice. In addition, expression of genes related to hepatic TG secretion was downregulated, with reduced hepatic TG secretion in MffLiKO mice in vivo and in primary cultures of MFF-deficient hepatocytes in vitro. Furthermore, thapsigargin-induced ER stress suppressed TG secretion in primary hepatocytes isolated from control mice. Conclusions/interpretation We demonstrated that ablation of MFF in liver provoked ER stress and reduced hepatic TG secretion in vivo and in vitro. Moreover, MffLiKO mice were more susceptible to HFD-induced NASH phenotype than control mice, partly because of ER stress-induced apoptosis of hepatocytes and suppression of TG secretion from hepatocytes. This study provides evidence for the role of mitochondrial fission in the development of NASH. Graphical abstract

The modified mitochondrial outer membrane carrier MTCH2 links mitochondrial fusion to lipogenesis

2021 ◽  
Vol 220 (11) ◽  
Author(s):  
Katherine Labbé ◽  
Shona Mookerjee ◽  
Maxence Le Vasseur ◽  
Eddy Gibbs ◽  
Chad Lerner ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fusion ◽  
Mitochondrial Outer Membrane ◽  
Mitochondrial Carrier ◽  
Cellular Survival ◽  
Mitochondrial Elongation ◽  
Specific Lipid

Mitochondrial function is integrated with cellular status through the regulation of opposing mitochondrial fusion and division events. Here we uncover a link between mitochondrial dynamics and lipid metabolism by examining the cellular role of mitochondrial carrier homologue 2 (MTCH2). MTCH2 is a modified outer mitochondrial membrane carrier protein implicated in intrinsic cell death and in the in vivo regulation of fatty acid metabolism. Our data indicate that MTCH2 is a selective effector of starvation-induced mitochondrial hyperfusion, a cytoprotective response to nutrient deprivation. We find that MTCH2 stimulates mitochondrial fusion in a manner dependent on the bioactive lipogenesis intermediate lysophosphatidic acid. We propose that MTCH2 monitors flux through the lipogenesis pathway and transmits this information to the mitochondrial fusion machinery to promote mitochondrial elongation, enhanced energy production, and cellular survival under homeostatic and starvation conditions. These findings will help resolve the roles of MTCH2 and mitochondria in tissue-specific lipid metabolism in animals.

scholarly journals T-2 Toxin-Induced Oxidative Stress Leads to Imbalance of Mitochondrial Fission and Fusion to Activate Cellular Apoptosis in the Human Liver 7702 Cell Line

Toxins ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 43 ◽  
Author(s):  
Junhua Yang ◽  
Wenbo Guo ◽  
Jianhua Wang ◽  
Xianli Yang ◽  
Zhiqi Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Apoptosis ◽  
Human Liver ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Mitochondrial Dynamic ◽  
Normal Human Liver ◽  
Induced Apoptosis

T-2 toxin, as a highly toxic mycotoxin to humans and animals, induces oxidative stress and apoptosis in various cells and tissues. Apoptosis and mitochondrial fusion/fission are two tightly interconnected processes that are crucial for maintaining physiological homeostasis. However, the role of mitochondrial fusion/fission in apoptosis of T-2 toxin remains unknown. Hence, we aimed to explore the putative role of mitochondrial fusion/fission on T-2 toxin induced apoptosis in normal human liver (HL-7702) cells. T-2 toxin treatment (0, 0.1, 1.0, or 10 μg/L) for 24 h caused decreased cell viability and ATP concentration and increased production of (ROS), as seen by a loss of mitochondrial membrane potential (∆Ψm) and increase in mitochondrial fragmentation. Subsequently, the mitochondrial dynamic imbalance was activated, evidenced by a dose-dependent decrease and increase in the protein expression of mitochondrial fusion (OPA1, Mfn1, and Mfn2) and fission (Drp1 and Fis1), respectively. Furthermore, the T-2 toxin promoted the release of cytochrome c from mitochondria to cytoplasm and induced cell apoptosis triggered by upregulation of Bax and Bax/Bcl-2 ratios, and further activated the caspase pathways. Taken together, these results indicate that altered mitochondrial dynamics induced by oxidative stress with T-2 toxin exposure likely contribute to mitochondrial injury and HL-7702 cell apoptosis.

scholarly journals Role of GTPase-Dependent Mitochondrial Dynamins in Heart Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Jiangen Liu ◽  
Xianjing Song ◽  
Youyou Yan ◽  
Bin Liu
Keyword(s):  
Cell Function ◽  
Morphological Changes ◽  
Heart Function ◽  
Mitochondrial Dynamics ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Dependent Manner

Heart function maintenance requires a large amount of energy, which is supplied by the mitochondria. In addition to providing energy to cardiomyocytes, mitochondria also play an important role in maintaining cell function and homeostasis. Although adult cardiomyocyte mitochondria appear as independent, low-static organelles, morphological changes have been observed in cardiomyocyte mitochondria under stress or pathological conditions. Indeed, cardiac mitochondrial fission and fusion are involved in the occurrence and development of heart diseases. As mitochondrial fission and fusion are primarily regulated by mitochondrial dynamins in a GTPase-dependent manner, GTPase-dependent mitochondrial fusion (MFN1, MFN2, and OPA1) and fission (DRP1) proteins, which are abundant in the adult heart, can also be regulated in heart diseases. In fact, these dynamic proteins have been shown to play important roles in specific diseases, including ischemia-reperfusion injury, heart failure, and metabolic cardiomyopathy. This article reviews the role of GTPase-dependent mitochondrial fusion and fission protein-mediated mitochondrial dynamics in the occurrence and development of heart diseases.

Abstract 20707: Macrophage Mitochondrial Fission is Essential for Continued Clearance of Apoptotic Cells and Plays a Protective Role in Advanced Atherosclerosis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Ying Wang ◽  
Ira Tabas ◽  
Masatoshi Nomura
Keyword(s):  
Mitochondrial Dynamics ◽  
Uncoupling Protein ◽  
Mitochondrial Fission ◽  
Myeloid Cell ◽  
Protective Role ◽  
Mitochondrial Fusion ◽  
Apoptotic Cells ◽  
Mitochondrial Dynamic ◽  
Inner Membrane

Introduction: The mitochondrial dynamic processes of fission and fusion influence and integrate with multiple physiologic and pathophysiologic processes. Mitochondrial dynamics dysregulation has been implicated in atherosclerosis, but little is known about the role of myeloid cell specific mitochondrial dynamics in the progression of atherosclerosis. In macrophage-enriched murine atherosclerosis lesion areas, we have found that levels of mitochondrial fission protein DRP1 down-regulated as the lesion progresses. In contrast, the mitochondrial fusion protein MFN2 is up-regulated. Further, mitochondria in lesional macrophages show hyperfusion morphology as the lesion develops. These suggest that mitochondria in macrophages undergo hyperfusion during the lesion progression. Hypothesis: We hypothesize that mitochondrial hyperfusion plays a significant role in atherosclerosis. Methods: We used a model Drp1fl/fl LysmCre+/-Ldlr-/-mice who have hyperfused mitochondria in Mϕs to test the functional significance of mitochondrial hyperfusion in atherosclerosis. Results: We have found that inhibition of Mϕ mitochondrial fission leads to a striking increase of necrotic core area and the accumulation of apoptotic cells, which are likely due to the defective phagocytic clearance of apoptotic cells (efferocytosis) in the advanced stage of atherosclerosis in vivo. This is further verified by another in vivo efferocytosis assay: Drp1fl/fl LysmCre+/-mice are defective of clearing apoptotic thymocytes in vivo. Mechanistically, the continued uptake of apoptotic cellsis impaired in Mϕs with hyperfused mitochondria. This is because of the lower level of uncoupling protein 2 (UCP2), the mitochondrial inner membrane protein that prevents the sustained elevation of inner membrane potential (Δψ). Chemical uncoupler FCCP or restoration of UCP2 can correct the efferocytosis deficiency in DRP1 knockout Mϕs. Conclusions: Macrophage mitochondrial fission is essential for continued clearance of apoptotic cells and plays a protective role in advanced atherosclerosis. This study indicates that mitochondrial fusion/fission could be a novel therapeutic target to prevent lesion necrosis and stabilize the advanced plaques in humans.

scholarly journals Dynamin-related protein 1 deficiency impairs mitophagy and accelerates lipopolysaccharide-induced inflammation in mice

2020 ◽  
Author(s):  
Lixiang Wang ◽  
Xin Li ◽  
Yuki Hanada ◽  
Nao Hasuzawa ◽  
Masatoshi Nomura ◽  
...  
Keyword(s):  
Liver Disease ◽  
Disease Progression ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Inflammasome Activation ◽  
Disease Development ◽  
Related Protein ◽  
Liver Disease Progression

Abstract Mitochondrial fusion and fission, which are strongly related to normal mitochondrial function, are referred to as mitochondrial dynamics. Mitochondrial fusion defects in the liver cause a non-alcoholic steatohepatitis-like phenotype and liver cancer. However, whether mitochondrial fission defect directly impair liver function and stimulate liver disease progression, too, is unclear. Dynamin-related protein 1 (DRP1) is a key factor controlling mitochondrial fission. We hypothesized that DRP1 defects are a causal factor directly involved in liver disease development and stimulate liver disease progression. We administered lipopolysaccharide (LPS) to liver-specific Drp1-knockout (Drp1LiKO) mice. We observed an enhanced inflammatory response accompanied by mitophagy impairment. Drp1 defects directly promoted hepatocyte apoptosis and subsequently induced infiltration of inflammatory macrophages enhanced inflammasome activation in the liver and increased pro-inflammatory cytokine expression in the liver and serum. Drp1 deletion increased the expression of numerous genes involved in the immune response and DNA damage in Drp1LiKO mouse primary hepatocytes. This is a novel mechanism of liver disease development in which Drp1 defect-induced mitochondrial dynamics dysfunction directly regulates the fate and function of hepatocytes and enhances LPS-induced acute liver injure in vivo.

scholarly journals Dynamin-Related Protein 1 Deficiency Promotes Recovery from AKI

2017 ◽  
Vol 29 (1) ◽  
pp. 194-206 ◽  
Author(s):  
Heather M. Perry ◽  
Liping Huang ◽  
Rebecca J. Wilson ◽  
Amandeep Bajwa ◽  
Hiromi Sesaki ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Mitochondrial Function ◽  
Ischemia Reperfusion Injury ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Kidney Injury ◽  
Related Protein

The proximal tubule epithelium relies on mitochondrial function for energy, rendering the kidney highly susceptible to ischemic AKI. Dynamin-related protein 1 (DRP1), a mediator of mitochondrial fission, regulates mitochondrial function; however, the cell-specific and temporal role of DRP1 in AKI in vivo is unknown. Using genetic murine models, we found that proximal tubule–specific deletion of Drp1 prevented the renal ischemia-reperfusion–induced kidney injury, inflammation, and programmed cell death observed in wild-type mice and promoted epithelial recovery, which associated with activation of the renoprotective β-hydroxybutyrate signaling pathway. Loss of DRP1 preserved mitochondrial structure and reduced oxidative stress in injured kidneys. Lastly, proximal tubule deletion of DRP1 after ischemia-reperfusion injury attenuated progressive kidney injury and fibrosis. These results implicate DRP1 and mitochondrial dynamics as an important mediator of AKI and progression to fibrosis and suggest that DRP1 may serve as a therapeutic target for AKI.

scholarly journals Aberrant mitochondrial fission in neurons induced by protein kinase Cδ under oxidative stress conditions in vivo

2011 ◽  
Vol 22 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Xin Qi ◽  
Marie-Helene Disatnik ◽  
Ning Shen ◽  
Raymond A. Sobel ◽  
Daria Mochly-Rosen
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitochondrial Fragmentation ◽  
Neurological Pathology ◽  
Protein Kinase Cδ

Neuronal cell death in a number of neurological disorders is associated with aberrant mitochondrial dynamics and mitochondrial degeneration. However, the triggers for this mitochondrial dysregulation are not known. Here we show excessive mitochondrial fission and mitochondrial structural disarray in brains of hypertensive rats with hypertension-induced brain injury (encephalopathy). We found that activation of protein kinase Cδ (PKCδ) induced aberrant mitochondrial fragmentation and impaired mitochondrial function in cultured SH-SY5Y neuronal cells and in this rat model of hypertension-induced encephalopathy. Immunoprecipitation studies indicate that PKCδ binds Drp1, a major mitochondrial fission protein, and phosphorylates Drp1 at Ser 579, thus increasing mitochondrial fragmentation. Further, we found that Drp1 Ser 579 phosphorylation by PKCδ is associated with Drp1 translocation to the mitochondria under oxidative stress. Importantly, inhibition of PKCδ, using a selective PKCδ peptide inhibitor (δV1-1), reduced mitochondrial fission and fragmentation and conferred neuronal protection in vivo and in culture. Our study suggests that PKCδ activation dysregulates the mitochondrial fission machinery and induces aberrant mitochondrial fission, thus contributing to neurological pathology.

scholarly journals Mitochondrial dynamics during spermatogenesis

2020 ◽  
Vol 133 (14) ◽  
pp. jcs235937
Author(s):  
Grigor Varuzhanyan ◽  
David C. Chan
Keyword(s):  
Germ Line ◽  
Mitochondrial Dynamics ◽  
High Energy ◽  
Mitochondrial Fusion ◽  
Developmental Systems ◽  
Developmentally Regulated ◽  
Energy Demands ◽  
Normal Cellular Function

ABSTRACTMitochondrial fusion and fission (mitochondrial dynamics) are homeostatic processes that safeguard normal cellular function. This relationship is especially strong in tissues with constitutively high energy demands, such as brain, heart and skeletal muscle. Less is known about the role of mitochondrial dynamics in developmental systems that involve changes in metabolic function. One such system is spermatogenesis. The first mitochondrial dynamics gene, Fuzzy onions (Fzo), was discovered in 1997 to mediate mitochondrial fusion during Drosophila spermatogenesis. In mammals, however, the role of mitochondrial fusion during spermatogenesis remained unknown for nearly two decades after discovery of Fzo. Mammalian spermatogenesis is one of the most complex and lengthy differentiation processes in biology, transforming spermatogonial stem cells into highly specialized sperm cells over a 5-week period. This elaborate differentiation process requires several developmentally regulated mitochondrial and metabolic transitions, making it an attractive model system for studying mitochondrial dynamics in vivo. We review the emerging role of mitochondrial biology, and especially its dynamics, during the development of the male germ line.

scholarly journals The intramitochondrial dynamin-related GTPase, Mgm1p, is a component of a protein complex that mediates mitochondrial fusion

2003 ◽  
Vol 160 (3) ◽  
pp. 303-311 ◽  
Author(s):  
Edith D. Wong ◽  
Jennifer A. Wagner ◽  
Sidney V. Scott ◽  
Voytek Okreglak ◽  
Timothy J. Holewinske ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Mitochondrial Fission ◽  
Mitochondrial Fusion ◽  
Intermembrane Space ◽  
Inner Membrane ◽  
Self Assembling ◽  
Novel Method ◽  
Membrane Components

Abalance between fission and fusion events determines the morphology of mitochondria. In yeast, mitochondrial fission is regulated by the outer membrane–associated dynamin-related GTPase, Dnm1p. Mitochondrial fusion requires two integral outer membrane components, Fzo1p and Ugo1p. Interestingly, mutations in a second mitochondrial-associated dynamin-related GTPase, Mgm1p, produce similar phenotypes to fzo1 and ugo cells. Specifically, mutations in MGM1 cause mitochondrial fragmentation and a loss of mitochondrial DNA that are suppressed by abolishing DNM1-dependent fission. In contrast to fzo1ts mutants, blocking DNM1-dependent fission restores mitochondrial fusion in mgm1ts cells during mating. Here we show that blocking DNM1-dependent fission in Δmgm1 cells fails to restore mitochondrial fusion during mating. To examine the role of Mgm1p in mitochondrial fusion, we looked for molecular interactions with known fusion components. Immunoprecipitation experiments revealed that Mgm1p is associated with both Ugo1p and Fzo1p in mitochondria, and that Ugo1p and Fzo1p also are associated with each other. In addition, genetic analysis of specific mgm1 alleles indicates that Mgm1p's GTPase and GTPase effector domains are required for its ability to promote mitochondrial fusion and that Mgm1p self-interacts, suggesting that it functions in fusion as a self-assembling GTPase. Mgm1p's localization within mitochondria has been controversial. Using protease protection and immuno-EM, we have shown previously that Mgm1p localizes to the intermembrane space, associated with the inner membrane. To further test our conclusions, we have used a novel method using the tobacco etch virus protease and confirm that Mgm1p is present in the intermembrane space compartment in vivo. Taken together, these data suggest a model where Mgm1p functions in fusion to remodel the inner membrane and to connect the inner membrane to the outer membrane via its interactions with Ugo1p and Fzo1p, thereby helping to coordinate the behavior of the four mitochondrial membranes during fusion.

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