Polo-like kinases mediate cell survival in mitochondrial dysfunction

Matsumoto, Takumi; Wang, Ping-yuan; Ma, Wenzhe; Sung, Ho Joong; Matoba, Satoaki; Hwang, Paul M.

doi:10.1073/pnas.0904229106

Cited by 71 publications

(75 citation statements)

References 36 publications

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“…Because metformin has pleiotropic effects on cells, we utilized a pair of isogenic respiratory-proficient and -deficient cell lines to demonstrate that its antiproliferation effect acts via inhibition of respiration. Metformin inhibited the proliferation of wild-type human colon cancer HCT116 cells, but did not markedly affect nonrespiring cells with homozygous deletion of synthesis of cytochrome c oxidase 2 (SCO2 -/-), an essential factor for the assembly of respiratory complex IV (Figure 2A) (20). In parallel, metformin reproduced the in vivo cell signaling changes caused by mitochondrial disruption only in respiring SCO2 +/+ cells ( Figure 2B).…”

Section: Gsk/cyclin D1 Pathway In Approximately 1-year-old Heterozygomentioning

confidence: 49%

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Wang¹,

Li²,

Walcott³

et al. 2016

Journal of Clinical Investigation

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Section: Gsk/cyclin D1 Pathway In Approximately 1-year-old Heterozygomentioning

confidence: 49%

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome

Wang¹,

Li²,

Walcott³

et al. 2016

Journal of Clinical Investigation

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“…Disruption of SCO2 eliminates mitochondrial respiration, 31 and overexpression of SCO2 augments mitochondrial respiration. 13 We showed, using SCO2 (ϩ/Ϫ) mice, the marked decreases in SCO2 expression and mitochondrial respiration compared with the wild-type mice ( Figure 5).…”

Section: Discussionmentioning

confidence: 99%

p53 Promotes Cardiac Dysfunction in Diabetic Mellitus Caused by Excessive Mitochondrial Respiration-Mediated Reactive Oxygen Species Generation and Lipid Accumulation

Nakamura

Matoba

Iwai-Kanai

et al. 2012

Circ: Heart Failure

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Background-Diabetic cardiomyopathy is characterized by energetic dysregulation caused by glucotoxicity, lipotoxicity, and mitochondrial alterations. p53 and its downstream mitochondrial assembly protein, synthesis of cytochrome c oxidase 2 (SCO2), are important regulators of mitochondrial respiration, whereas the involvement in diabetic cardiomyopathy remains to be determined. Methods and Results-The role of p53 and SCO2 in energy metabolism was examined in both type I (streptozotocin [STZ] administration) and type II diabetic (db/db) mice. Cardiac expressions of p53 and SCO2 in 4-week STZ diabetic mice were upregulated (185% and 152% versus controls, respectively, PϽ0.01), with a marked decrease in cardiac performance. Mitochondrial oxygen consumption was increased (136% versus control, PϽ0.01) in parallel with augmentation of mitochondrial cytochrome c oxidase (complex IV) activity. Reactive oxygen species (ROS)-damaged myocytes and lipid accumulation were increased in association with membrane-localization of fatty acid translocase protein FAT/CD36. Antioxidant tempol reduced the increased expressions of p53 and SCO2 in STZ-diabetic hearts and normalized alterations in mitochondrial oxygen consumption, lipid accumulation, and cardiac dysfunction. Similar results were observed in db/db mice, whereas in p53-deficient or SCO2-deficient diabetic mice, the cardiac and metabolic abnormalities were prevented. Overexpression of SCO2 in cardiac myocytes increased mitochondrial ROS and fatty acid accumulation, whereas knockdown of SCO2 ameliorated them. Conclusions-Myocardial p53/SCO2 signal is activated by diabetes-mediated ROS generation to increase mitochondrial oxygen consumption, resulting in excessive generation of mitochondria-derived ROS and lipid accumulation in association with cardiac dysfunction. (Circ Heart Fail. 2012;5:106-115.)Key Words: cardiomyopathy Ⅲ diabetes mellitus Ⅲ metabolism Ⅲ heart failure Ⅲ free radicals Ⅲ mitochondria D iabetic cardiomyopathy is one of the leading causes of increased morbidity and mortality in the patients with diabetes mellitus. 1,2 Although the pathogenesis of this cardiac contractile dysfunction is still unclear, an involvement of increased reactive oxygen species (ROS) production 3 and altered mitochondrial function 4,5 have been reported. Mitochondrial uncoupling was shown to be a possible mechanism to reduce cardiac efficiency in type 2 diabetes models 6 but not in type 1 diabetes models. 7 Recent study using positron emission tomography in patients with type 1 diabetes mellitus has revealed the Clinical Perspective on p 115increased oxygen consumption and altered fatty acid (FA) metabolism. 8 These human and animal studies have shown that increased oxidative stress correlates with lipid overload, Received February 9, 2011; accepted October 31, 2011. From the Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto, Japan (H.N., S.M., E.I.-K., M. Kimata, A.H., M. Katamura, Y.O., M.A., Y.M., K.I....

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“…Therefore, studying bioenergetics in intact cells may provide a more physiological view of mitochondrial function. Recently, bioenergetic profiling of intact cells has been described in multiple cell lines (1,9,14,16) and primary cells (6,7,10,11,20,21,28) using a microplate-based system that measures extracellular flux (XF). This automated system measures the two major cellular energyproducing pathways, glycolysis and mitochondrial respiration.…”

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confidence: 99%