Mycophenolic acid inhibits oleic acid-induced mesangial cell activation through both cellular reactive oxygen species and inosine monophosphate dehydrogenase 2 pathways

As the powerhouse of the cell for producing adenosine triphosphate (ATP), the “energy currency” for energizing aerobic life, the mitochondrion is also a major source of cellular reactive oxygen species (ROS) production. Cutting-edge research studies over the past few years have uncovered a series of previously unrecognized fundamental biological functions carried out by mitochondrial ROS. Among them is the regulation of immunity by mitochondrial ROS signaling. (First online: Mar 13, 2021) REFERENCES Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al. Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005; 308(5730):1909–11. doi: https://dx.doi.org/10.1126/science.1106653. Dai DF, Santana LF, Vermulst M, Tomazela DM, Emond MJ, MacCoss MJ, et al. Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation 2009; 119(21):2789–97. doi: https://dx.doi.org/10.1161/CIRCULATIONAHA.108.822403. Lee HY, Choi CS, Birkenfeld AL, Alves TC, Jornayvaz FR, Jurczak MJ, et al. Targeted expression of catalase to mitochondria prevents age-associated reductions in mitochondrial function and insulin resistance. Cell Metab 2010; 12(6):668–74. doi: https://dx.doi.org/10.1016/j.cmet.2010.11.004. Chouchani ET, Pell VR, Gaude E, Aksentijevic D, Sundier SY, Robb EL, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515(7527):431–5. doi: https://dx.doi.org/10.1038/nature13909. Nickel AG, von Hardenberg A, Hohl M, Loffler JR, Kohlhaas M, Becker J, et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab 2015; 22(3):472–84. doi: https://dx.doi.org/10.1016/j.cmet.2015.07.008. Shadel GS, Horvath TL. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015; 163(3):560–9. doi: https://dx.doi.org/10.1016/j.cell.2015.10.001. Mills EL, Kelly B, Logan A, Costa ASH, Varma M, Bryant CE, et al. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 2016; 167(2):457–70 e13. doi: https://dx.doi.org/10.1016/j.cell.2016.08.064. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 2011; 472(7344):476–80. doi: https://dx.doi.org/10.1038/nature09973. Geng J, Sun X, Wang P, Zhang S, Wang X, Wu H, et al. Kinases Mst1 and Mst2 positively regulate phagocytic induction of reactive oxygen species and bactericidal activity. Nat Immunol 2015; 16(11):1142–52. doi: https://dx.doi.org/10.1038/ni.3268. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013; 38(2):225–36. doi: https://dx.doi.org/10.1016/j.immuni.2012.10.020. Oberkampf M, Guillerey C, Mouries J, Rosenbaum P, Fayolle C, Bobard A, et al. Mitochondrial reactive oxygen species regulate the induction of CD8+ T cells by plasmacytoid dendritic cells. Nat Commun 2018; 9(1):2241. doi: https://dx.doi.org/10.1038/s41467-018-04686-8. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 2016; 531(7593):253–7. doi: https://dx.doi.org/10.1038/nature16969. Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol 2021; 22(2):205–15. doi: https://dx.doi.org/10.1038/s41590-020-00834-9.

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Faculty Opinions recommendation of Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717982005.793472527 ◽

2013 ◽

Author(s):

Cosima Tatiana Baldari ◽

Laura Patrussi

Keyword(s):

Reactive Oxygen Species ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Reactive Oxygen ◽

Oxygen Species ◽

Reactive Oxygen Species Signaling

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The β-adrenoceptor agonist isoproterenol promotes the activity of respiratory chain complex I and lowers cellular reactive oxygen species in fibroblasts and heart myoblasts

European Journal of Pharmacology ◽

10.1016/j.ejphar.2010.11.016 ◽

2011 ◽

Vol 652 (1-3) ◽

pp. 15-22 ◽

Cited By ~ 25

Author(s):

Domenico De Rasmo ◽

Giuliano Gattoni ◽

Francesco Papa ◽

Arcangela Santeramo ◽

Consiglia Pacelli ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Respiratory Chain ◽

Complex I ◽

Reactive Oxygen ◽

Chain Complex ◽

Oxygen Species ◽

Respiratory Chain Complex ◽

Adrenoceptor Agonist ◽

Cellular Reactive Oxygen Species

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Doxorubicin-Induced Fetal Mesangial Cell Death Occurs Independently of TRPC6 Channel Upregulation but Involves Mitochondrial Generation of Reactive Oxygen Species

International Journal of Molecular Sciences ◽

10.3390/ijms22147589 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7589

Author(s):

Anberitha T. Matthews ◽

Hitesh Soni ◽

Katherine E. Robinson-Freeman ◽

Theresa A. John ◽

Randal K. Buddington ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Cell Death ◽

Transient Receptor Potential ◽

Mesangial Cell ◽

Reactive Oxygen ◽

Receptor Potential ◽

Oxygen Species ◽

Glomerular Mesangial Cell ◽

Trpc6 Channel ◽

Fetal Pig

Doxorubicin (DOX), a category D pregnancy drug, is a chemotherapeutic agent that has been shown in animal studies to induce fetal toxicity, including renal abnormalities. Upregulation of the transient receptor potential cation (TRPC) 6 channel is involved in DOX-induced podocyte apoptosis. We have previously reported that TRPC6-mediated Ca2+ signaling promotes neonatal glomerular mesangial cell (GMC) death. However, it is unknown whether DOX alters mesangial TRPC expression or viability in the fetus. In this study, cell growth was tracked in control and DOX-treated primary GMCs derived from fetal pigs. Live-cell imaging demonstrated that exposure to DOX inhibited the proliferation of fetal pig GMCs and induced cell death. DOX did not alter the TRPC3 expression levels. By contrast, TRPC6 protein expression in the cells was markedly reduced by DOX. DOX treatment also attenuated the TRPC6-mediated intracellular Ca2+ elevation. DOX stimulated mitochondrial reactive oxygen species (mtROS) generation and mitophagy by the GMCs. The DOX-induced mtROS generation and apoptosis were reversed by the mitochondria-targeted antioxidant mitoquinone. These data suggest that DOX-induced fetal pig GMC apoptosis is independent of TRPC6 channel upregulation but requires mtROS production. The mtROS-dependent GMC death may contribute to DOX-induced fetal nephrotoxicity when administered prenatally.

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