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Identification of an mtDNA Mutation Hot Spot in UV-Induced Mouse Skin Tumors Producing Altered Cellular Biochemistry  Jana Jandova, Alex Eshaghian, Mingjian.

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Presentation on theme: "Identification of an mtDNA Mutation Hot Spot in UV-Induced Mouse Skin Tumors Producing Altered Cellular Biochemistry  Jana Jandova, Alex Eshaghian, Mingjian."— Presentation transcript:

1 Identification of an mtDNA Mutation Hot Spot in UV-Induced Mouse Skin Tumors Producing Altered Cellular Biochemistry  Jana Jandova, Alex Eshaghian, Mingjian Shi, Meiling Li, Lloyd E. King, Jaroslav Janda, James E. Sligh  Journal of Investigative Dermatology  Volume 132, Issue 2, Pages (February 2012) DOI: /jid Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

2 Figure 1 Induced cutaneous tumors and frequency of point mutation in the mt-Tr locus (tRNAArg). (a) Dorsal surface of a hairless mouse with UV-induced cutaneous tumors. (b) Hematoxylin and eosin histology stain of one of these tumors is consistent with a diagnosis of squamous papilloma. The height of the papilloma equals 2mm. (c) The percentage of samples with various diagnoses harboring a mutant mt-Tr 9821insA allele is shown. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

3 Figure 2 Restriction analysis, temperature gradient capillary electrophoresis (TGCE) multiplex analysis, and DNA sequencing detect mtDNA mutation hot spot. (a) Resolution of undigested PCR products covering the entire mtDNA (left) and digested restriction fragments (right) are shown in an inverted image of a 1.5% agarose gel stained with ethidium bromide. (b) TGCE output from a single capillary. Unknown (from a tumor, top), control (bottom), and mixed (center) mouse DNA samples were analyzed. Fragments 1, 3, and 4 have only a single peak, which is indicative of complete homoduplex formation and the lack of a mutation. The presence of an additional peak for fragment 2 in the unknown and mixed samples is indicative of heteroduplex formation and the detection of a somatic mutation. (c) The gel image of all four fragments. DNA sequencing of the mt-Tr locus in control and tumor DNA samples in reverse orientation. (d) Partial DNA sequence of wild-type allele and (e) homoplasmic or (f) heteroplasmic 9821insA mutant allele. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

4 Figure 3 Predicted transfer RNA (tRNA) structures based on sequence. The predicted structures for the tRNA variants generated by mfold software. (a) Wild-type tRNA isoform with ΔG=-9.8kcalmol−1, (b) 9821insA tRNA isoform with ΔG=-9.8kcalmol−1, and (c) 9821insA tRNA isoform with ΔG=-11.3kcalmol−1. Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

5 Figure 4 The mtBALB cybrid cells have lower adenosine triphosphate (ATP) production and altered respiratory function compared with mtB6 cybrids. (a) Cybrid cells were incubated in DMEM supplemented with either glucose or galactose. The levels of cellular ATP are shown. (b) Fiber optic investigation of mitochondrial respiratory chain function showing oxygen consumption was performed without the addition of an exogenous substrate, and with the addition of specific oxidative phosphorylation (OXPHOS) substrates or inhibitors. Values represent the mean±SEM of three independent experiments of five clones. CCCP, carbonyl cyanide m-chlorophenylhydrazone. Asterisks indicate statistical difference between mtB6 and mtBALB cybrid cells (*P<0.05, **P<0.005). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

6 Figure 5 Complex I levels are lower in mtBALB cybrid cells compared with mtB6. (a) Five mouse monoclonal antibodies to mitochondrial oxidative phosphorylation (OXPHOS) subunits were used to detect protein levels by western blot analysis. (b) Densitometry of western blot analysis showing reduced levels of complex I protein. The level of complex I, II, III, IV, and V subunits is expressed as the relative intensity of the immunoblots normalized to β-actin loading control. Data are mean±SEM of three independent experiments of five clones. Asterisk indicates statistical difference between mtB6 and mtBALB cybrid cells (*P<0.05). Journal of Investigative Dermatology  , DOI: ( /jid ) Copyright © 2012 The Society for Investigative Dermatology, Inc Terms and Conditions

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