scholarly journals Disturbance of Mitochondrial Dynamics and Mitochondrial Therapies in Atherosclerosis

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 165
Author(s):  
Alexander M. Markin ◽  
Viktoria A. Khotina ◽  
Xenia G. Zabudskaya ◽  
Anastasia I. Bogatyreva ◽  
Antonina V. Starodubova ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Energy Production ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Living Cells ◽  
Therapeutic Approaches ◽  
Energy Needs ◽  
Wide Range ◽  
Human Disorders ◽  
Mitochondrial Turnover

Mitochondrial dysfunction is associated with a wide range of chronic human disorders, including atherosclerosis and diabetes mellitus. Mitochondria are dynamic organelles that undergo constant turnover in living cells. Through the processes of mitochondrial fission and fusion, a functional population of mitochondria is maintained, that responds to the energy needs of the cell. Damaged or excessive mitochondria are degraded by mitophagy, a specialized type of autophagy. These processes are orchestrated by a number of proteins and genes, and are tightly regulated. When one or several of these processes are affected, it can lead to the accumulation of dysfunctional mitochondria, deficient energy production, increased oxidative stress and cell death—features that are described in many human disorders. While severe mitochondrial dysfunction is known to cause specific and mitochondrial disorders in humans, progressing damage of the mitochondria is also observed in a wide range of other chronic diseases, including cancer and atherosclerosis, and appears to play an important role in disease development. Therefore, correction of mitochondrial dynamics can help in developing new therapies for the treatment of these conditions. In this review, we summarize the recent knowledge on the processes of mitochondrial turnover and the proteins and genes involved in it. We provide a list of known mutations that affect mitochondrial function, and discuss the emerging therapeutic approaches.

scholarly journals High glucose induces Drp1-mediated mitochondrial fission via the Orai1 calcium channel to participate in diabetic cardiomyocyte hypertrophy

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Qing-Rui Wu ◽  
Dan-Lin Zheng ◽  
Pei-Ming Liu ◽  
Hui Yang ◽  
Lu-An Li ◽  
...  
Keyword(s):  
Calcium Channel ◽  
Mitochondrial Dysfunction ◽  
High Glucose ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Calcium Handling ◽  
Cardiomyocyte Hypertrophy ◽  
Mitochondrial Morphology ◽  
Calmodulin Binding ◽  
Downstream Target

AbstractMitochondrial dysfunction and impaired Ca2+ handling are involved in the development of diabetic cardiomyopathy (DCM). Dynamic relative protein 1 (Drp1) regulates mitochondrial fission by changing its level of phosphorylation, and the Orai1 (Ca2+ release-activated calcium channel protein 1) calcium channel is important for the increase in Ca2+ entry into cardiomyocytes. We aimed to explore the mechanism of Drp1 and Orai1 in cardiomyocyte hypertrophy caused by high glucose (HG). We found that Zucker diabetic fat rats induced by administration of a high-fat diet develop cardiac hypertrophy and impaired cardiac function, accompanied by the activation of mitochondrial dynamics and calcium handling pathway-related proteins. Moreover, HG induces cardiomyocyte hypertrophy, accompanied by abnormal mitochondrial morphology and function, and increased Orai1-mediated Ca2+ influx. Mechanistically, the Drp1 inhibitor mitochondrial division inhibitor 1 (Mdivi-1) prevents cardiomyocyte hypertrophy induced by HG by reducing phosphorylation of Drp1 at serine 616 (S616) and increasing phosphorylation at S637. Inhibition of Orai1 with single guide RNA (sgOrai1) or an inhibitor (BTP2) not only suppressed Drp1 activity and calmodulin-binding catalytic subunit A (CnA) and phosphorylated-extracellular signal-regulated kinase (p-ERK1/2) expression but also alleviated mitochondrial dysfunction and cardiomyocyte hypertrophy caused by HG. In addition, the CnA inhibitor cyclosporin A and p-ERK1/2 inhibitor U0126 improved HG-induced cardiomyocyte hypertrophy by promoting and inhibiting phosphorylation of Drp1 at S637 and S616, respectively. In summary, we identified Drp1 as a downstream target of Orai1-mediated Ca2+ entry, via activation by p-ERK1/2-mediated phosphorylation at S616 or CnA-mediated dephosphorylation at S637 in DCM. Thus, the Orai1–Drp1 axis is a novel target for treating DCM.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

Mitochondrial Changes and Bioenergetics in Neurodegenerative Diseases

2016 ◽  
Author(s):  
Andrew B. Knott ◽  
Ella Bossy-Wetzel
Keyword(s):  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Energy Production ◽  
Mitochondrial Dynamics ◽  
Calcium Handling ◽  
Mitochondrial Proteins ◽  
Genetic Mutations ◽  
Critical Importance ◽  
Cellular Survival ◽  
Dna Mutations

Mitochondria are dynamic organelles that are of critical importance for cellular survival and health. Because mitochondria play central roles in energy production and synaptic maintenance, neurons are believed to be particularly vulnerable to mitochondrial dysfunction. The discovery that genetic mutations in genes coding for mitochondrial proteins cause neurodegenerative conditions further hinted at the likelihood that mitochondrial dysfunction is a key pathway of neurodegeneration. Indeed, a wealth of research has identified mitochondrial dysfunction as an early and shared event of all common neurodegenerative diseases, both genetic and sporadic in origin. Specific types of mitochondrial dysfunction that have been observed in most neurodegenerative diseases include bioenergetic failure, increased oxidative stress, mitochondrial DNA mutations, defective calcium handling, impaired mitochondrial dynamics, defective mitophagy, and decreased mitochondrial biogenesis. The search for drugs that successfully target these pathways of mitochondrial dysfunction in neurodegeneration is ongoing.

Abstract 392: Angiotensin II TypeI Receptor-mediated Mitochondrial Fission and Suppression of Mitophagy Play Crucial Role in Vascular Senescence and Arteriosclerosis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Double Knockout ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Metabolic stress including oxidized low density lipoprotein (ox-LDL) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that undergo quality control by mitochondrial dynamics and mitophagy. This study aims to clarify whether and how mitochondrial dynamics and mitophagy are involved in the etiology of vascular senescence and arteriosclerosis. Methods: VSMC were stimulated by ox-LDL. We also conducted in vivo experiment using C57BL6 (WT), apolipoprotein E (ApoE) deficient and the double knockout of ApoE mice and Angiotensin II Type1 Receptor (AT1R). Results: Treatment of ox-LDL forced mitochondria to fission through activation of Drp1, induced mitochondrial dysfunction and oxidative stress, and developed cellular senescence. Inhibition of either Drp1, AT1R, MAPK retarded them, suggesting that mitochondrial fission plays key roles to develop premature cellular senescence and is modulated by AT1R/MAPK signal.Administration of ox-LDL decreased the number of mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R signal inhibition increased mitophagy which was not affected by Atg7 knockdown, whereas it was decreased by either Rab9 or Ulk1 knockdown. Immunohistochemistry showed Rab9 dots were co-localized to TOMM20 and LAMP2, whereas LC3 dots were not, suggesting that AT1R signal induces mitophagy through Rab9-dependent alternative autophagy. The degree of vascular senescence was higher, the number of fused mitochondria and mitochondrial function were lower and mitochondrial oxidative stress was higher in ApoE KO than those in WT. DKO attenuated these adverse effect of ApoE KO. Conclusion: AT1R regulates vascular senescence and arteriosclerosis via induction of mitochondrial fission and inhibition of mitophagy.

scholarly journals Squamosamide Derivative FLZ Diminishes Aberrant Mitochondrial Fission by Inhibiting Dynamin-Related Protein 1

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanyu Yang ◽  
Lu Wang ◽  
Caixia Zang ◽  
Xu Yang ◽  
Xiuqi Bao ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Motor Coordination ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Mitochondrial Morphology ◽  
Protective Effects ◽  
Related Protein ◽  
Mitochondrial Fragmentation

Mitochondrial dysfunction is involved in the pathogenesis of Parkinson’s disease (PD). Mitochondrial morphology is dynamic and precisely regulated by mitochondrial fission and fusion machinery. Aberrant mitochondrial fragmentation, which can result in cell death, is controlled by the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Our previous results demonstrated that FLZ could correct mitochondrial dysfunction, but the effect of FLZ on mitochondrial dynamics remain uncharacterized. In this study, we investigated the effect of FLZ and the role of Drp1 on 1-methyl-4-phenylpyridinium (MPP+)–induced mitochondrial fission in neurons. We observed that FLZ blocked Drp1, inhibited Drp1 enzyme activity, and reduced excessive mitochondrial fission in cultured neurons. Furthermore, by inhibiting mitochondrial fission and ROS production, FLZ improved mitochondrial integrity and membrane potential, resulting in neuroprotection. FLZ curtailed the reduction of synaptic branches of primary cultured dopaminergic neurons caused by MPP+ exposure, reduced abnormal fission, restored normal mitochondrial distribution in neurons, and exhibited protective effects on dopaminergic neurons. The in vitro research results were validated using an MPTP-induced PD mouse model. The in vivo results revealed that FLZ significantly reduced the mitochondrial translocation of Drp1 in the midbrain of PD mice, which, in turn, reduced the mitochondrial fragmentation in mouse substantia nigra neurons. FLZ also protected dopaminergic neurons in PD mice and increased the dopamine content in the striatum, which improved the motor coordination ability of the mice. These findings elucidate this newly discovered mechanism through which FLZ produces neuroprotection in PD.

scholarly journals Mitochondrial Dysfunction in Intervertebral Disc Degeneration: From Pathogenesis to Therapeutic Target

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Danni Li ◽  
Fenghua Tao ◽  
Lin Jin
Keyword(s):  
Intervertebral Disc ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Cascade Reactions ◽  
Great Promise ◽  
Ros Generation ◽  
Current State ◽  
Ivd Degeneration

Mitochondria are cytosolic organelles essential for cellular function and survival. The function of mitochondria is maintained by mitochondrial quality control systems including mitochondrial fission and fusion to adapt the altered environment and mitophagy for removal of damaged mitochondria. Mitochondrial dysfunction is closely involved in aging-related diseases. Intervertebral disc (IVD) degeneration, an aging-associated process, is the major contributor to low back pain. Growing evidence has suggested that the mitochondrial function in IVD cells is severely compromised during the degenerative process of IVD, and dysfunctional mitochondria along with impaired mitochondrial dynamics and mitophagy cause a series of cascade reactions that have been implicated in increased oxidative stress, senescence, matrix catabolism, and apoptosis of IVD cells, thereby contributing to the degeneration of IVD. Accordingly, therapies that target mitochondrial dysfunction and related mechanisms, such as ROS generation, mitophagy, and specific molecules and signaling, hold great promise. The present review summarizes the current state of the role of mitochondrial dysfunction in the pathophysiology of IVD degeneration and potential therapeutic strategies that could be developed.

scholarly journals Mitochondrial Dynamics: Molecular Mechanisms, Related Primary Mitochondrial Disorders and Therapeutic Approaches

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 247
Author(s):  
Michela Di Nottia ◽  
Daniela Verrigni ◽  
Alessandra Torraco ◽  
Teresa Rizza ◽  
Enrico Bertini ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
The Other ◽  
Fusion Process ◽  
Therapeutic Approaches ◽  
Pathological Conditions ◽  
Opposite Process ◽  
Neurogenetic Disorders ◽  
Guanosine Triphosphatase

Mitochondria do not exist as individual entities in the cell—conversely, they constitute an interconnected community governed by the constant and opposite process of fission and fusion. The mitochondrial fission leads to the formation of smaller mitochondria, promoting the biogenesis of new organelles. On the other hand, following the fusion process, mitochondria appear as longer and interconnected tubules, which enhance the communication with other organelles. Both fission and fusion are carried out by a small number of highly conserved guanosine triphosphatase proteins and their interactors. Disruption of this equilibrium has been associated with several pathological conditions, ranging from cancer to neurodegeneration, and mutations in genes involved in mitochondrial fission and fusion have been reported to be the cause of a subset of neurogenetic disorders.

Abstract 198: Metabolic Stress Causes Mitochondrial Dysfunction and Vascular Senescence via Angiotensin II Type I Receptor Signal / Rho Kinase Induced Mitochondrial Fission

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Rho Kinase ◽  
Metabolic Stress ◽  
In Vitro Experiments ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Metabolic stress, such as oxidized low density lipoprotein (ox-LDL) and advanced glycation end products (AGE) cause mitochondrial dysfunction and evoke vascular senescence and atherosclerosis. Mitochondria are highly dynamic organelles that constantly change their morphology to fusion or fission. This study aims to clarify whether mitochondrial dynamics is involved in the etiology of vascular senescence. Methods: We used C57BL6 (WT), apolipoprotein E deficient (ApoE KO) and db/db mice. We also conducted in vitro experiments using VSMC and HUVEC. Results: The degree of arterial senescence, arterial protein level of Drp1 in mitochondrial fraction and mitochondrial oxidative stress were higher and the number of fused mitochondria and mitochondrial function were lower in either ApoE KO or db/db mice than those of WT mice. Treatment with Drp1-specific inhibitor, mdivi-1, to these mice reduced excessive mitochondrial fission, oxidative stress and attenuated vascular senescence. Administration of either ox-LDL or AGE to cells also induced excessive mitochondrial fission though phosphorylation of Drp1 at Ser616, mitochondrial dysfunction, reactive oxygen species production and cellular senescence. Treatment with mdivi-1 to these cells restored imbalance of mitochondrial dynamics and these detrimental alterations. These results suggest that metabolic stress-induced mitochondrial dysfunction and cellular senescence were derived from Drp1-dependent mitochondrial fission. Treatment with angiotensin II type1 receptor (AT1R) blocker (ARB) to either Apo E KO mice or db/db in in vivo experiments and administration of ARB to cells with ox-LDL or AGE stimulation in in vitro experiments inactivated Drp1 and improved imbalance of mitochondrial dynamics, mitochondrial dysfunction and cellular senescence, suggesting that AT1R signal is involved in regulating metabolic stress-induced mitochondrial fission. Finally, inhibition of Rho kinase ROCK1 successfully attenuated Drp1-mediated mitochondrial fission and cellular senescence derived from metabolic stress. Conclusion: Metabolic stress causes cellular and vascular senescence through AT1R signal/Rho kinase-mediated mitochondrial fission.

Abstract 15506: Inhibition of Angiotensin II Type I Receptor Induces Dual Modification of Mitochondrial Dynamics and Mitophagy via Inactivation of Ras/raf/mek Pathway and Contributes Vascular Anti-senescence

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yoshihiro Uchikado ◽  
Yoshiyuki Ikeda ◽  
Yuichi Sasaki ◽  
Yuichi Akasaki ◽  
Mitsuru Ohishi
Keyword(s):  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Type I ◽  
Ang Ii ◽  
Double Knockout ◽  
Apoe Ko ◽  
Vascular Senescence

Introduction: Angiotensin II (Ang II) causes vascular senescence by damaging mitochondria that undergo quality control by mitochondrial dynamics and mitophagy. We examined whether and how AngII type I receptor (AT1R) signal regulates mitochondrial dynamics and mitophagy in the etiology of vascular senescence. Methods: We used vascular smooth muscle cells (VSMC) and C57BL6 (WT), apolipoprotein E deficient (ApoE KO) and the double knockout of ApoE and AT1R mice. Results: Administration of Ang II to VSMC forced mitochondria to fission and induced cellular senescence and mitochondrial dysfunction, which were restored by inhibition of fission by use of Mdivi-1. Treatment of ox-LDL also induced cellular senescence accompanied by excessive mitochondrial fission through phosphorylation of Drp1 at Ser616 and mitochondrial dysfunction. These alterations were ameliorated by inhibition of AT1R signal, suggesting that AT1R signal inhibition may contribute anti-cellular senescence by modification of mitochondrial dynamics. AT1R signal inhibition also induced mitophagy assessed by electron microscopy and immunohistochemistry of LAMP2 and TOMM20. AT1R inhibition-induced mitophagy was not affected by Atg7 Knockdown, whereas it was diminished by Rab9 knockdown. Immunohistochemistry showed TOMM20 dots were co-localized to LAMP2 and Rab9 but not LC3. These results suggest that AT1R signal induces mitophagy derived from Rab9-dependent alternative autophagy. Treatment of ox-LDL activated Ras, Raf and MEK, and AT1R inhibition inactivated them. Inhibition of Ras/Raf/MEK decreased excessive mitochondrial fission and induced mitophagy, suggesting that AT1R signal followed by Ras/Raf/MEK pathway modulates both mitochondrial dynamics and mitophagy. The degree of arterial senescence and atherosclerosis, Drp1 expression in mitochondrial fraction and oxidative stress in artery were higher and the number of mitophagy, fused mitochondria and its function were lower in ApoE KO than those of WT mice. AT1R KO to ApoE KO attenuated these adverse effects of ApoE KO. Conclusions: Inhibition of AT1R signal contributes vascular senescence through modification of mitochondrial dynamics and mitophagy by inactivation of Ras/Raf/MEK pathway.

Abstract 5379: Increased Myocardial Fatty Acid Uptake by Acyl-CoA Synthetase 1 Impairs Mitochondrial Function and Dynamics

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Heiko Bugger ◽  
Xiao Xuan Hu ◽  
Joseph Tuinei ◽  
Heather Theobald ◽  
William L Holland ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Mitochondrial Membrane ◽  
Morphological Changes ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Atp Synthesis ◽  
Fatty Acid Uptake ◽  
Membrane Lipid ◽  
Acid Uptake

Increased uptake and oxidation of fatty acids (FA) in diabetic hearts may contribute to mitochondrial dysfunction by promoting oxidative stress. To test this hypothesis, we investigated mice with cardiomyocyte-restricted overexpression of long-chain acyl-CoA synthetase 1 (MHC-ACS). In vivo PET studies revealed increased myocardial FA uptake (+120%; p<0.05) in MHC-ACS. Unexpectedly, FA oxidation and myocellular triglyceride content were unchanged, and PPARα-regulated FAO genes and PGC-1α-regulated OXPHOS genes were unaltered. However, cardiac content of the phospholipid precursors ceramide (+260%; p<0.05) and diacylglycerol (+40%; p<0.05) were increased. Mitochondrial cardiolipin content was decreased (−25%; p<0.05) and remodeled with substitution of 18:2 FA chains by unsaturated 22:6 FAs. Both ADP-stimulated mitochondrial O2 consumption (14.3±0.9 vs. 16.8±0.5 nmol/min/mgdw; p<0.05) and ATP synthesis (24.2±1.4 vs. 31.8±1.6 nmol/min/mgdw; p<0.05) were decreased in MHC-ACS in saponin-permeabilized cardiac fibers using palmitoyl-carnitine as a substrate. Mitochondrial superoxide production was increased by 75% (p<0.05). Electron microscopy in 3 to 24 week-old mice revealed increased mitochondrial number, which was highest at 3 weeks (3wk +210%, 12wk +120%, 24wk +130%; all p<0.05), and reduced mitochondrial size. Translocation of the mitochondrial fission protein dynamin-related protein 1 (Drp1) from cytosol to mitochondria was absent (p<0.05) in MHC-ACS, but not in controls. Mitochondrial membrane content of the fission protein fission 1 and the fusion proteins mitofusin 1 and 2 were unchanged. These morphological changes are consistent with increased mitochondrial fission and reduced Drp1 likely represents an adaptive response. Thus remodeling of the myocardial lipid pool and mitochondrial membrane lipid composition are associated with impaired mitochondrial dynamics and represents a novel mechanism for lipid-induced mitochondrial dysfunction in the heart.

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