scholarly journals Mitophagy and Mitochondrial Dysfunction in Cancer

2020 ◽  
Vol 4 (1) ◽  
pp. 41-60 ◽  
Author(s):  
Kay F. Macleod
Keyword(s):  
Mitochondrial Dysfunction ◽  
Cell Fate ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Oxygen Species ◽  
Tumor Cell Growth ◽  
Mitochondrial Mass ◽  
Cell Fate Decisions ◽  
Signaling Mechanisms ◽  
Altered Cell

The process of mitophagy, in which mitochondria are selectively turned over at the autophagolysosome, plays a central role in both eliminating dysfunctional mitochondria and reducing mitochondrial mass as an adaptive response to key physiological stresses, such as hypoxia, nutrient deprivation, and DNA damage. Defects in mitophagy have been linked to altered mitochondrial metabolism, production of excess reactive oxygen species and ferroptosis, heightened inflammasome activation, altered cell fate decisions, and senescence, among other cellular consequences. Consequently, functional mitophagy contributes to proper tissue differentiation and repair and metabolic homeostasis, limiting inflammatory responses and modulating tumor progression and metastasis. This review examines the major pathways that control mitophagy, including PINK1-dependent mitophagy and BNIP3/NIX-dependent mitophagy. It also discusses the cellular signaling mechanisms used to sense mitochondrial dysfunction to activate mitophagy and how defective mitophagy results in deregulated tumor cell growth and cancer.

Notch1-Induced Delay of Human Hematopoietic Progenitor Cell Differentiation Is Associated With Altered Cell Cycle Kinetics

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 838-848 ◽  
Author(s):  
Nadia Carlesso ◽  
Jon C. Aster ◽  
Jeffrey Sklar ◽  
David T. Scadden
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cell Fate ◽  
Active Form ◽  
Hematopoietic Progenitor Cell ◽  
Cell Phenotype ◽  
Cell Cycle Kinetics ◽  
Cell Fate Decisions ◽  
Cd34 Cells ◽  
Altered Cell

Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood–derived CD34+ cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34+ cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34+ cells. In addition, primary CD34+cells retained their ability to form immature colonies, colony-forming unit–mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.

scholarly journals Dysregulation of redox pathways in liver fibrosis

2016 ◽  
Vol 311 (4) ◽  
pp. G667-G674 ◽  
Author(s):  
Natalie J. Torok
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Fate ◽  
Liver Diseases ◽  
Oxygen Species ◽  
Chronic Liver Diseases ◽  
Cell Fate Decisions ◽  
Novel Treatment ◽  
Antioxidant Mechanisms ◽  
Precise Role

Reactive oxygen species are implicated in physiological signaling and cell fate decisions. In chronic liver diseases persistent and increased production of oxidative radicals drives a fibrogenic response that is a common feature of disease progression. Despite our understanding the biology of the main prooxidant enzymes, their targets, and antioxidant mechanisms in the liver, there is still lack of knowledge concerning their precise role in the pathogenesis of fibrosis. This review will examine the role of physiological redox signaling in the liver, provide an overview on recent advances in prooxidant and antioxidant pathways that are dysregulated during fibrosis, and highlight possible novel treatment targets.

scholarly journals CoQ10 ameliorates mitochondrial dysfunction in diabetic nephropathy through mitophagy

2019 ◽  
Vol 240 (3) ◽  
pp. 445-465 ◽  
Author(s):  
Jia Sun ◽  
Haiping Zhu ◽  
Xiaorong Wang ◽  
Qiuqi Gao ◽  
Zhuoying Li ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Mitochondrial Dysfunction ◽  
Nuclear Translocation ◽  
Oxygen Species ◽  
Molecular Signaling ◽  
Mitochondrial Reactive Oxygen Species ◽  
Beneficial Effects ◽  
Signaling Mechanisms ◽  
Effective Antioxidant ◽  
Expression Activity

The molecular signaling mechanisms of Coenzyme Q10 (CoQ10) in diabetic nephropathy (DN) remain poorly understood. We verified that mitochondrial abnormalities, like defective mitophagy, the generation of mitochondrial reactive oxygen species (mtROS) and the reduction of mitochondrial membrane potential, occurred in the glomerulus of db/db mice, accompanied by reduced PINK and parkin expression and increased apoptosis. These changes were partially reversed following oral administration of CoQ10. In inner fenestrated murine glomerular endothelial cells (mGECs), high glucose (HG) also resulted in deficient mitophagy, mitochondrial dysfunction and apoptosis, which were reversed by CoQ10. Mitophagy suppression mediated by Mdivi-1 or siPINK abrogated the renoprotective effects exerted by CoQ10, suggesting a beneficial role for CoQ10-restored mitophagy in DN. Mechanistically, CoQ10 restored the expression, activity and nuclear translocation of Nrf2 in HG-cultured mGECs. In addition, the reduced PINK and parkin expression observed in HG-cultured mGECs were partially elevated by CoQ10. CoQ10-mediated renoprotective effects were abrogated by the Nrf2 inhibitor ML385. When ML385 abolished mitophagy and the renoprotective effects exerted by CoQ10, mGECs could be rescued by treatment with mitoTEMPO, which is a mtROS-targeted antioxidant. These results suggest that CoQ10, as an effective antioxidant in mitochondria, exerts beneficial effects in DN via mitophagy by restoring Nrf2/ARE signaling. In summary, CoQ10-mediated mitophagy activation positively regulates DN through a mechanism involving mtROS, which influences the activation of the Nrf2/ARE pathway.

scholarly journals Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Liu Ye ◽  
Qi Zeng ◽  
Maoyao Ling ◽  
Riliang Ma ◽  
Haishao Chen ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Lung Injury ◽  
Er Stress ◽  
Mitochondrial Dysfunction ◽  
Nlrp3 Inflammasome ◽  
Inflammatory Responses ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Ventilator Induced Lung Injury ◽  
Nlrp3 Inflammasome Activation

RationaleDisruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model.MethodsC57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines.ResultsLungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction.ConclusionIncrease in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.

Notch1-Induced Delay of Human Hematopoietic Progenitor Cell Differentiation Is Associated With Altered Cell Cycle Kinetics

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 838-848 ◽  
Author(s):  
Nadia Carlesso ◽  
Jon C. Aster ◽  
Jeffrey Sklar ◽  
David T. Scadden
Keyword(s):  
Cell Cycle ◽  
Cord Blood ◽  
Cell Fate ◽  
Active Form ◽  
Hematopoietic Progenitor Cell ◽  
Cell Phenotype ◽  
Cell Cycle Kinetics ◽  
Cell Fate Decisions ◽  
Cd34 Cells ◽  
Altered Cell

Abstract Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood–derived CD34+ cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34+ cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34+ cells. In addition, primary CD34+cells retained their ability to form immature colonies, colony-forming unit–mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.

p53-Mediated Stress and Tissue-Dependent Cell Fate Decisions; Implications for p53 Targeting

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-3-SCI-3
Author(s):  
Guillermina (Gigi) Lozano
Keyword(s):  
Cell Fate ◽  
Ubiquitin Ligase ◽  
Conflicts Of Interest ◽  
Oxygen Species ◽  
Antioxidant Treatment ◽  
Cell Fate Decisions ◽  
Hypomorphic Allele ◽  
Cell Cycle Inhibitor ◽  
Dependent Cell

Abstract Abstract SCI-3 The activity of the p53 tumor suppressor is tightly regulated by Mdm2, an E3 ubiquitin ligase that targets p53 for degradation. Loss of Mdm2 in embryos or in individual tissues in vivo results in cell lethal events that are p53-dependent. A hypomorphic allele of p53, p53515C (encoding the p53R172P protein), rescues the embryonic lethality of Mdm2–/– mice. Mdm2–/– p53515C/515C mice, however, die by postnatal day 13 due to hematopoietic failure. In these mice, hematopoiesis is normal during embryogenesis. After birth, these mice had elevated reactive oxygen species (ROS), which activated p53R172P. p53R172P, in turn, induced ROS, creating a loop that caused cell death in the hematopoietic compartment. This phenotype was partially rescued with antioxidant treatment. The cell cycle inhibitor, p16, was also stabilized due to ROS, and its loss increased cell cycling and partially rescued hematopoiesis and survival. Thus, Mdm2 is required to control ROS-induced p53 levels for sustainable hematopoiesis. Disclosures: No relevant conflicts of interest to declare.

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