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Research Article
The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts
Vedad Delic, Kenyaria Noble, Sandra Zivkovic, Tam-Anh Phan, Christian Reynes, Yumeng Zhang, Oluwakemi Phillips, Charles Claybaker, Yen Ta, Vinh B. Dinh, Josean Cruz, Tomas A. Prolla, Patrick C. Bradshaw
Biology Open 2018 7: bio033852 doi: 10.1242/bio.033852 Published 16 November 2018
Vedad Delic
1Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama Birmingham School of Medicine, Birmingham, AL 35233, USA
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Kenyaria Noble
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Sandra Zivkovic
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Tam-Anh Phan
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Christian Reynes
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Yumeng Zhang
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
3Department of Internal Medicine, University of South Florida, Tampa, FL 33606, USA
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Oluwakemi Phillips
4University of South Florida College of Medicine, Department of Molecular Pharmacology and Physiology, Tampa, FL 33612, USA
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Charles Claybaker
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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  • ORCID record for Charles Claybaker
Yen Ta
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Vinh B. Dinh
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Josean Cruz
2Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL 33620, USA
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Tomas A. Prolla
5Department of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA
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Patrick C. Bradshaw
6Department of Biomedical Sciences, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
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  • ORCID record for Patrick C. Bradshaw
  • For correspondence: bradshawp@etsu.edu
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    Fig. 1.

    Sensitivity of WT and MtDNA mutator (POLGexo−) MEFs to mitochondrial toxins. Mitochondrial mutator MEFs were more sensitive than WT MEFs to inhibition of colony formation by azide (P=0.025), ethidium bromide (P=0.046), FCCP (P=0.002) and chloramphenicol (P<0.001). A very strong trend for a difference in sensitivity was also found for rotenone (P=0.053). Colony counting assays were performed to determine IC50 values for (A) azide, (B) ethidium bromide (EtBr), (C) tert-butyl hydroperoxide, (D) rotenone, (E) antimycin A, (F) hydrogen peroxide (H2O2), (G) FCCP, (H) oligomycin, and (I) chloramphenicol. Experiments were performed with three independently derived E1A immortalized WT and mtDNA mutator clone lines (n=3). Bars represent mean±s.e.m. Unpaired t-tests were performed with * indicating a P-value of <0.05 and ** indicating a P-value <0.001.

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    Fig. 2.

    O2 consumption rates of WT and POLGexo− MEFs treated with AICAR or rapamycin. (A) O2 consumption rates after 24 h in HGM. (B) O2 consumption rates after 48 h in HGM. (C) O2 consumption rates after 24 h in LGPM. (D) O2 consumption rates after 30 h in LGPM. (E) O2 consumption rates after 10 days in HGPUM. (F) O2 consumption rates after 20 days in HGPUM. Rapamycin transiently increases oxygen consumption in WT MEFs at the 24 h time point either in the absence or presence of pyruvate. Respiratory deficits in POLGexo− MEFs were revealed by the LGPM used in panels C and D and the HGPUM used in panels E and F. Experiments were repeated twice using three technical replicates each time. Bars represent mean±s.e.m. Two-way ANOVA with Fisher's LSD post hoc analysis was performed. *P<0.05, **P<0.001.

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    Fig. 3.

    Effects of AICAR or rapamycin on ROS production of WT and POLGexo− MEFs under low glucose conditions. Rapamycin treatment in LGM or LGPM had no effect on ROS production. 0.5% ethanol (EtOH) was added as a positive control to induce ROS production. (A) ROS levels after 24 h in LGM. (B) ROS levels after 48 h in LGM. (C) ROS levels after 24 h in LGPM. (D) ROS levels after 48 h in LGPM. Experiments were repeated twice using five technical replicates each time. Bars represent mean±s.e.m. Two-way ANOVA with Fisher's LSD post hoc analysis was performed. *P<0.05, **P<0.001.

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    Fig. 4.

    Effects of AICAR or rapamycin on ROS production of WT and POLGexo− MEFs under high glucose conditions. 0.5% ethanol (EtOH) was added as a positive control to induce ROS production. (A) ROS levels after 24 h in HGM. (B) ROS levels after 48 h in HGM. (C) ROS levels after 24 h in HGPM. (D) ROS levels after 48 h in HGPM. (E) ROS levels after 10 days in HGPUM. (F) ROS levels after 20 days in HGPUM. Experiments were repeated twice using five technical replicates each time. Bars represent mean±s.e.m. Two-way ANOVA with Fisher's LSD post hoc analysis was performed. *P<0.05, **P<0.001.

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    Fig. 5.

    Effects of AICAR or rapamycin on ATP levels of WT and POLGexo− MEFs under low glucose conditions. (A) ATP levels after 24 h in LGM. (B) ATP levels after 48 h in LGM. (C) ATP levels after 24 h in LGPM. (D) ATP levels after 48 h in LGPM. Experiments were repeated twice using five technical replicates each time. Bars represent mean±s.e.m. Two-way ANOVA with Fisher's LSD post hoc analysis was performed. *P<0.05, **P<0.001.

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    Fig. 6.

    Effects of AICAR or rapamycin on ATP levels of WT and POLGexo− MEFs under high glucose conditions. (A) ATP levels after 24 h in HGM. (B) ATP levels after 48 h in HGM. (C) ATP levels after 24 h in HGPM. (D) ATP levels after 48 h in HGPM. (E) ATP levels after 10 days in HGPUM. (F) ATP levels after 20 days in HGPUM. Experiments were repeated twice using five technical replicates each time. Bars represent mean±s.e.m. Two-way ANOVA with Fisher's LSD post hoc analysis was performed. **P<0.001.

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Keywords

  • mTOR
  • AMP kinase
  • Aging
  • Mitochondria
  • Rapamycin
  • Pyruvate addiction

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Research Article
The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts
Vedad Delic, Kenyaria Noble, Sandra Zivkovic, Tam-Anh Phan, Christian Reynes, Yumeng Zhang, Oluwakemi Phillips, Charles Claybaker, Yen Ta, Vinh B. Dinh, Josean Cruz, Tomas A. Prolla, Patrick C. Bradshaw
Biology Open 2018 7: bio033852 doi: 10.1242/bio.033852 Published 16 November 2018
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Research Article
The effects of AICAR and rapamycin on mitochondrial function in immortalized mitochondrial DNA mutator murine embryonic fibroblasts
Vedad Delic, Kenyaria Noble, Sandra Zivkovic, Tam-Anh Phan, Christian Reynes, Yumeng Zhang, Oluwakemi Phillips, Charles Claybaker, Yen Ta, Vinh B. Dinh, Josean Cruz, Tomas A. Prolla, Patrick C. Bradshaw
Biology Open 2018 7: bio033852 doi: 10.1242/bio.033852 Published 16 November 2018

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