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The Journal of Immunology, 2003, 170: 3603-3607.
Copyright © 2003 by The American Association of Immunologists

Role of MHC Class I in Immune Surveillance of Mitochondrial DNA Integrity1

Yiping Gu2, Chunjie Wang2, Chaim M. Roifman and Amos Cohen3

Division of Immunology and Allergy, Departments of Pediatrics and Immunology, Infection, Immunity, Injury, and Repair Program, Research Institute, University of Toronto and Hospital for Sick Children, Toronto, Ontario, Canada


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Mitochondrial DNA is subject to increased rates of mutations due to its proximity to the source of reactive oxygen species. Here we show that increased MHC class I (MHC I) expression serves to alert the immune system to cells with mitochondrial mutations. MHC I is overexpressed in fibroblasts with mitochondrial dysfunction from patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes and in lymphocytes from purine nucleoside phosphorylase-deficient immune-deficient mice with mitochondrial DNA deletions. Consistent with a role of MHC I in the elimination of cells containing mitochondrial DNA mutations, mice deficient in MHC I accumulate mitochondrial DNA deletions in various tissues. These observations in both mice and humans suggest a role for the immune system in preventing reversion of mitochondrial DNA back into a parasitic state following deleterious mutations affecting mitochondrial oxidative phosphorylation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
As a result of its proximity to the primary source of reactive oxygen species (ROS)4 production, the mitochondrial genome is subject to a high mutation rate (1, 2). To prevent the accumulation of deleterious mitochondrial mutations, effective mechanisms evolved that eliminate cells with mitochondrial defects. A role of active immune surveillance of mitochondrial genome integrity is suggested by the accumulation of numerous mitochondrial DNA mutations in cases of immune failure such as occurs in cancer, degenerative diseases, and aging (3). However, the specific means of immune surveillance in maintaining the integrity of the mitochondrial genome has not been explored.

To investigate the role of the immune system in the maintenance of mitochondrial DNA, we generated purine nucleoside phosphorylase (PNP)-deficient mice. These mice exhibit immune deficiency caused by abnormalities in mitochondrial deoxynucleoside metabolism and accumulate abnormally high levels of dGTP specifically in the mitochondria (4). PNP deficiency is similar to other mitochondrial diseases in humans with enzyme deficiencies affecting mitochondrial deoxynucleotide metabolism, the cytosolic enzyme thymidine phosphorylase (5), and the mitochondrial enzymes thymidine kinase (6) and deoxyguanosine kinase (7). Deficiencies in these enzymes cause abnormalities in mitochondrial DNA in humans. However, no mitochondrial deletions or deleterious phenotype were found in thymidine phosphorylase and uridine phosphorylase double-knockout mice, suggesting differences in mitochondrial thymidine metabolism between humans and mice (8). Here we show that damaged mitochondrial DNA causes increased expression of MHC class I (MHC I), which may assist the immune system to eliminate cells with mitochondrial DNA mutations.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Flow cytometric analysis

Single-cell suspensions were stained with anti-mouse {beta}2-microglobulin Ab and with a second anti-IgG2b FITC-conjugated Ab (BD PharMingen, Mississauga, Canada). Fluorescent data were collected using logarithmic amplification on 50 x 103 viable cells as determined by forward/side scatter and propidium iodide exclusion. Since PNP-deficient mice express different MHC I haplotypes, {beta}2-microglobulin was used as the indicator of MHC I expression levels (similar results were obtained using anti-MHC Abs). ROS production was assessed fluorometrically using the oxidation-ensetive fluorescent probe 5,6-carboxy-2',7'-dichlorofluorescein diacetate (Molecular Probes, Eugene, OR) (9).

Cell cultures

Osteocarcinoma cell lines (American Type Culture Collection, Manassas, VA) were kept in continuous logarithmic growth in RPMI 1640 supplemented with sodium pyruvate (20 mM) with 10% FCS by subculturing them twice weekly at a concentration of 2 x 104 cells/cm2 with standard trypsinization. Cells were treated with IFN-{gamma} (2 IU/ml) for 72 h. Where indicated, cells were preincubated for 48 h in the presence of 10 mM N-acetyl cysteine (Nac).

Southern blot analysis of mitochondrial DNA

The entire mitochondrial DNA from 6-mo-old B57BL6 and {beta}2-microglobulin- or PNP-deficient mice was amplified by PCR using opposing primers as described in Fig. 1. The use of PCR with primers spanning the entire mitochondrial genome allows the detection of mitochondrial DNA deletions that appear as smaller bands or a smear when probed with mitochondrial DNA (10). The entire mitochondrial DNA from 3-mo-old B57BL6 and PNP-deficient mice was amplified by PCR using opposing primers located in the cytochrome {beta} gene (forward primer, 5'-caggtcttttcttagccatacactacacatcag-3'; reverse primer, 5'-gactattaggcgactcctagaagggacc-3'). The PCR consisted of an initial 2-min denaturation at 94°C, followed by two-step PCR for 30 cycles using 5-min annealing/extension at 68°C, 10-s denaturation at 94°C, and a final extension of 10 min at 72°C in a 9600 thermal cycler (PerkinElmer, Norwalk, CT). A 5-µl aliquot of the PCR was electrophoresed on 0.7% agarose and blotted on nitrocellulose. Gel-purified 32P-labeled full-length PCR product mitochondrial DNA was used for Southern hybridization.



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  		FIGURE 1. Southern blot analysis of mitochondrial DNA deletions of splenocytes from PNP-deficient and wild-type mice. Total DNA was extracted from splenocytes of 3-mo-old PNP-deficient and wild-type littermates. The entire mitochondrial DNA was amplified, blotted, and probed as described in Materials and Methods. Intact mitochondrial DNA is 16.5 kb; smaller size bands represent mitochondrial DNA with deletions of various sizes. Results are representative of experiments performed with three pairs of mice.

 
Western blotting

Exponentially growing 143B and Rho0 cells were treated with IFN-{gamma} (2 IU/ml) for the indicated times. Where indicated, cells were preincubated for 48 h with 20 mM Nac. For Western blotting analysis cells were washed twice in cold PBS and lysed in lysis buffer (50 mM Tris-HCl (pH 7.5), 120 mM NaCl, 0.5% Nonidet P-40, 10 mM NaF, 1 mM Na3VO4, 1 mM DTT, 1 mM 4-(2-amino ethyl)-benzensulfonyl fluoride hydrochloride, 20 µg/ml leupeptin, and 20 µg/ml aprotinin). Lysates were incubated for 30 min on ice and clarified by centrifugation at 14,000 rpm for 2 min. The protein concentration was determined by Bio-Rad protein assay (Hercules, CA). Proteins were separated by SDS-PAGE and blotted onto Protan nitrocellulose membrane (Schleicher & Schuell, Keene, NH). Membranes were blocked for 1 h in TBST (20 mM Tris-HCl (pH 7.5), 138 mM NaCl, and 0.1% Tween 20) containing 5% nonfat milk at room temperature, probed with primary Ab for 1 h, washed three times with TBST, probed again with HRP-conjugated secondary Ab for 45 min, and washed again three times in TBST. The Ag-Ab reaction was revealed using ECL procedures according to the manufacturer’s recommendation (Pierce, Rockford, IL). Phospho-Stat1 (Tyr701) Ab was purchased from Cell Signaling Technology (Beverly, MA).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To determine whether the abnormal accumulation of dGTP in the mitochondria of PNP-deficient lymphocytes (4) affects the integrity of mitochondrial DNA, we monitored mitochondrial DNA deletions in splenocytes from PNP-deficient mice (Fig. 1). Similar to cells from patients with deficiencies of similar deoxynucleoside metabolic enzymes, such as the cytosolic enzyme thymidine phosphorylase or the mitochondrial enzymes thymidine and deoxyguanosine kinase, lymphocytes from PNP-deficient mice accumulate mitochondrial DNA deletions (5). These deletions could be a direct result of PNP deficiency or, alternatively, could result from the secondary loss of mitochondrial deoxyguanosine kinase in these mice (4).

Similar to PNP-deficient patients, PNP knockout mice suffer from immune deficiency and autoimmunity phenotype (4, 11). As increased expression of MHC class I can cause autoimmunity (12), we determined the surface expression of MHC I on lymphocytes from PNP-deficient mice. Splenocytes from PNP-deficient mice exhibit abnormally high levels of MHC I molecules expressed on their cell surface (Fig. 2). These observations led us to hypothesize that cells with mutations and deletions in mitochondrial DNA may alert the immune system by increasing the expression of MHC I molecules on their surface.



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  		FIGURE 2. Flow cytometric analysis of MHC I expression on the surface of splenocytes from PNP-deficient and wild-type littermates. Splenocyte single-cell suspensions were stained with anti-mouse {beta}2-microglobulin Ab or isotype control Ab (faint line) and with a second anti IgG2b FITC-conjugated Ab (BD PharMingen). Fluorescent data were collected using logarithmic amplification on 50 x 103 viable cells as determined by forward/side scatter and propidium iodide exclusion as described in Materials and Methods. The lower chart represents PNP-deficient lymphocytes, and the upper chart represents wild-type cells. Three additional experiments yielded similar results.

 
To investigate the mechanisms by which abnormalities in mitochondrial DNA may affect MHC I expression, we studied the expression of MHC I in osteosarcoma Rho0 cells deficient in mitochondrial DNA compared with their parental line 143B with a normal mitochondrial genome (13). Lack of mitochondrial DNA in Rho0 cells is associated with slightly higher surface expression of MHC I (2-fold) compared with 143B cells with a normal mitochondrial genome (Fig. 3a). Moreover, MHC I expression is markedly increased in Rho0 cells (10-fold) compared with 143B cells in response to IFN-{gamma} stimulation (Fig. 3b). The changes in MHC I expression correlate well with similar changes in its mRNA expression (data not shown).



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  		FIGURE 3. Regulation of MHC I expression by IFN-{gamma} and Nac in osteosarcoma cells deficient in mitochondrial DNA (Rho0) and their parental cell line 143B. Osteocarcinoma cells were treated with IFN-{gamma} (2 IU/ml) for 72 h. Where indicated, cells were preincubated for 48 h in the presence of 20 mM Nac. Cell suspensions were stained with anti-human {beta}2-microglobulin Abs and with a second anti-IgG2b FITC-conjugated Ab (BD PharMingen). Fluorescent data were collected using logarithmic amplification on 50 x 103 viable cells as determined by forward/side scatter and propidium iodide exclusion as described in Materials and Methods. Results are representative of four separate experiments.

 
We next determined the mechanism by which abnormalities in mitochondrial DNA affect the expression of MHC I. Since cells without a mitochondrial genome lack both an active electron transport chain and oxidative phosphorylation, we determined whether these cells release abnormally low levels of ROS (Fig. 4). Osteosarcoma cells that lack mitochondrial DNA release abnormally low levels of ROS independent of the level of expression of the apoptosis protective protein BCL2. To determine whether the increase in MHC I induction by IFN-{gamma} may be affected by the cellular oxidative state, we treated Rho0 or 143B cells with a reducing agent, Nac, a precursor of glutathione that can actively capture ROS produced by the electron transport chain (14). Nac has little effect on the basal expression of MHC I (Fig. 3c), but significantly promotes the expression of MHC I in IFN-{gamma}-treated 143B cells to levels comparable to those in Rho0 cells (Fig. 3d). The induction of MHC I by the combination of IFN-{gamma} and Nac in 143B cells is comparable to that achieved by IFN-{gamma} alone in Rho0 cells, suggesting that the increased induction by IFN-{gamma} in cells without mitochondrial DNA compared with wild-type cells is accounted for fully by differences in ROS production.



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  		FIGURE 4. Flow cytometric analysis of ROS production by osteosarcoma cells. The production of ROS was assessed by the oxidation-sensitive fluorescent probe 5,6-carboxy-2',7'-dichlorofluorescein diacetate in Rho0 and wild-type osteosarcoma cells and their BCL2 stable transfectants as described in Materials and Methods. Results are representative of four separate experiments.

 
IFN-{gamma} induces the expression of a number of cellular genes using the Janus tyrosine kinase-STAT pathway (15). To investigate whether elevated STAT-1 activation is associated with the increased induction of MHC I expression, we monitored the levels of STAT-1 phosphorylation following IFN-{gamma} treatment of 143B and Rho0 osteosarcoma cells (Fig. 5). IFN-{gamma} treatment of 143B cells causes a rapid phosphorylation of STAT-1 on tyrosine 701. The level of STAT-1 phosphorylation in Rho cells in response to IFN-{gamma} treatment is markedly increased (11-fold higher) compared with that in wild-type cells. Similar to the effects observed on MHC I expression, STAT-1 phosphorylation in response to IFN-{gamma} treatment was increased in the presence of Nac in wild-type cells, but not in Rho0 cells. Fluorescence microscopy revealed that phospho-STAT-1 was translocated to the nucleus in IFN-{gamma}-treated cells compared with 143B-treated cells (data not shown).



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  		FIGURE 5. Effects of IFN-{gamma} and Nac on STAT1 phosphorylation in osteosarcoma cells deficient in mitochondrial DNA (Rho0) and their parental cell line 143B. Exponentially growing 143B and Rho cells were treated with IFN-{gamma} (2 IU/ml) for the indicated times. Where indicated, cells were preincubated for 48 h with 20 mM Nac. Western blotting analysis was performed as described in Materials and Methods. Results are representative of three separate experiments.

 
The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated (MELAS) human mitochondrial tRNALeu(UUR) mutation causes reduced oxygen consumption at complex I (16). Cultured fibroblasts from patients with the MELAS syndrome express higher levels of MHC I on their surface in response to IFN-{gamma} treatment compared with fibroblasts from normal controls (Fig. 6).



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  		FIGURE 6. Effect of IFN-{gamma} on MHC I expression by cultured fibroblasts from a MELAS patient and a normal control. Fibroblast cultures were treated with IFN-{gamma} (20 IU/ml) for 72 h, and {beta}2-microglobulin expression was determined by flow cytometry as described in Materials and Methods. Similar results were obtained in two additional MELAS lines.

 
Increased expression of MHC I on cells with mitochondrial DNA mutations may facilitate the detection of corresponding altered mitochondrial peptides presented by MHC I molecules. Engagement of the altered peptides bound by MHC I by the TCR on cytotoxic T lymphocytes should result in elimination of cells with mitochondrial DNA mutations that resulted in altered peptides. To determine whether MHC I plays a role in the elimination of cells with mitochondrial mutations, we monitored the accumulation of mitochondrial DNA deletions in mice deficient in MHC I invariant chain ({beta}2-microglobulin-/-; Fig. 7). Mice deficient in MHC I expression demonstrate increased frequency of mitochondrial deletions in various tissues, including liver, spleen, and pancreas, compared with the corresponding tissues from wild-type mice.



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  		FIGURE 7. Southern blot analysis of PCR products of full-length mitochondrial DNA from tissues of {beta}2-microglobulin-deficient and wild-type mice. The entire mitochondrial DNA from 6-mo-old B56BL6 and {beta}-microglobulin deficient mice was amplified by PCR using opposing primers as described in Fig. 1.

 
Mitochondrial DNA is subject to increased mutation rate due to the proximity of oxidative phosphorylation and the excessive release of ROS (17). The mitochondrion is an endosymbiont that is believed to be related to {alpha}-proteobacteria such as Rickettsia and other obligate intracellular parasites (18). During the life of somatic cells individual mitochondrial DNA molecules may accumulate mutations and deletions eliminating the oxidative phosphorylation-related genes, while maintaining replicative capacity and thus reverting back to a parasitic state. However, despite the increased mutation rate during the life span of somatic cells, mitochondrial mutations are rarely observed in normal cells, suggesting active cellular processes that prevent the accumulation of mitochondrial mutations.

Several possible mechanisms may operate to preserve the integrity of the mitochondrial genome. These include mitochondrial DNA repair (19), apoptosis, and immune surveillance that eliminates cells with mutated mitochondrial DNA. Mutations that cause uncoupling or interruption of the electron transfer chain often result in increased ROS production, thus triggering cytochrome c release and cellular apoptosis (20, 21). On the other hand, mutations and deletions that reduce ROS production, such as disruption in complex III (22), are not expected to trigger cellular apoptosis. Cells harboring such mutations may survive unless removed by the immune system. MHC I has been shown to present various peptides derived from mitochondrial proteins to CD8+ T lymphocytes (23, 24). We propose that the increased induction by IFN-{gamma} of MHC I in cells with low ROS production facilitate the elimination of such cells by presenting mutated peptides to CD8+ cytotoxic T cells (Fig. 8).



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  		FIGURE 8. Roles of the immune system and apoptosis in the maintenance of mitochondrial DNA integrity.

 
Failure of the immune surveillance to delete altered proteins resulting from mitochondrial DNA mutations may help to explain a number of previously unexplained observations. There is an increased prevalence of mitochondrial mutations observed in cancer cells (25). These mutations may be due to the avoidance of immune surveillance caused by deficiency in MHC I function often associated with malignancies (26). A weakening of the immune system with old age may also account for the predominance of mitochondrial deletions observed during aging (27). The prevalence of autoimmune diseases, such as insulin-dependent diabetes mellitus, associated with mitochondrial diseases may be explained by increased MHC I expression due to decreased ROS production in these patients and subsequent development of autoimmunity (28, 29, 30). On the other hand, MHC I-deficient nonobese diabetic, {beta}2-microglobulin-null mice are diabetes and insulitis resistant (31).


   Acknowledgments
 
We thank Dr. John Chamberlain (The Hospital for Sick Children, Toronto, Canada) for the supply of {beta}2-microglobulin-/- mice, and Paul Doherty for critical reading of this manuscript.


   Footnotes
 
1 This work was supported partially by a grant from Canadian Institutes for Health Research (to A.C. and C.M.R.). Back

2 Y.G. and C.W. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Amos Cohen, The Hospital for Sick Children, Toronto, 555 University Avenue, Ontario, Canada M5G 1X8. E-mail address: ac{at}sickkids.on.ca Back

4 Abbreviations used in this paper: ROS, reactive oxygen species; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; Nac, N-acetyl cysteine; PNP, purine nucleoside phosphorylase; MHC I, MHC class I. Back

Received for publication October 15, 2002. Accepted for publication January 31, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Hofhaus, G., N. Gattermann. 1999. Mitochondria harbouring mutant mtDNA: a cuckoo in the nest?. J. Biol. Chem. 380:871.
  2. Denver, D. R., K. Morris, M. Lynch, L. L. Vassilieva, W. K. Thomas. 2000. High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans. Science 289:2342.[Abstract/Free Full Text]
  3. Berdanier, C. D., H. B. Everts. 2001. Mitochondrial DNA in aging and degenerative disease. Mut. Res. 475:169.[Medline]
  4. Arpaia, E., P. Benveniste, A. Di Cristofano, Y. Gu, I. Dalal, S. Kelly, M. Hershfield, P. P. Pandolfi, C. M. Roifman, A. Cohen. 2000. Mitochondrial basis for immune deficiency: evidence from purine nucleoside phosphorylase-deficient mice. J. Exp. Med. 191:2197.[Abstract/Free Full Text]
  5. Nishino, I., A. Spinazzola, M. Hirano. 1999. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283:689.[Abstract/Free Full Text]
  6. Saada, A.. 2001. Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy. Nat. Genet. 29:342.[Medline]
  7. Mandel, H., R. Szargel, V. Labay, O. Elpereg, A. Saada, A. Shalata, Y. Anbinder, D. Berkowich, C. Hartman, M. Barak, et al 2001. The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocellular mitochondrial DNA. Nat. Genet. 29:337.[Medline]
  8. Haraguchi, M., H. Tsujimoto, M. Fukushima, I. Higuchi, H. Kuribayashi, H. Utsumi, A. Nakayama, Y. Hashizume, J. Hirato, H. Yoshida, et al 2002. Targeted deletion of both thymidine phosphorylase and uridine phosphorylase and consequent disorders in mice. Mol. Cell. Biol. 22:5212.[Abstract/Free Full Text]
  9. Wartenberg, M., K. Fischer, J. Hescheler, H. Sauer. 2000. Redox regulation of P-glycoprotein-mediated multidrug resistance in multicellular prostate tumor spheroids. Intl. J. Cancer 85:267.[Medline]
  10. Melov, S.. 1995. Marked increase in the number and variety of mitochondrial DNA rearrangements in aging human skeletal muscle. [Published erratum appears in 1995 Nucleic Acids Res. 23:4938.]. Nucleic Acids Res. 23:4122.[Abstract/Free Full Text]
  11. Markert, M. L.. 1991. Purine nucleoside phosphorylase deficiency. Immunodefic. Rev. 3:45.[Medline]
  12. Singer, D. S., E. Mozes, S. Kirshner, L. D. Kohn. 1997. Role of MHC class I molecules in autoimmune disease. Crit. Rev. Immunol. 17:463.[Medline]
  13. Gilkerson, R. W., D. H. Margineantu, R. A. Capaldi, J. M. Selker. 2000. Mitochondrial DNA depletion causes morphological changes in the mitochondrial reticulum of cultured human cells. FEBS Lett. 474:1.[Medline]
  14. Deneke, S. M.. 2000. Thiol-based antioxidants. Curr. Top. Cell. Regul. 36:151.[Medline]
  15. Darnell, J. E., I. M. Kerr, G. R. Stark. 1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415.[Abstract/Free Full Text]
  16. Dunbar, D. R., P. A. Moonie, M. Zeviani, I. J. Holt. 1996. Complex I deficiency is associated with 3243G:C mitochondrial DNA in osteosarcoma cell hybrids. Hum. Mol. Gen. 5:123.[Abstract/Free Full Text]
  17. Lu, C. Y., H. C. Lee, H. J. Fahn, Y. H. Wei. 1999. Oxidative damage elicited by imbalance of free radical scavenging enzymes is associated with large-scale mtDNA deletions in aging human skin. Mut. Res. 423:11.[Medline]
  18. Gray, M. W., G. Burger, B. F. Lang. 1999. Mitochondrial evolution. Science 283:1476.[Abstract/Free Full Text]
  19. Croteau, D. L., R. H. Stierum, V. A. Bohr. 1999. Mitochondrial DNA repair pathways. Mut. Res. 434:137.[Medline]
  20. Wei, Y. H., C. Y. Lu, H. C. Lee, C. Y. Pang, Y. S. Ma. 1998. Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann. NY Acad. Sci. 854:155.[Medline]
  21. Esposito, L. A., S. Melov, A. Panov, B. A. Cottrell, D. C. Wallace. 1999. Mitochondrial disease in mouse results in increased oxidative stress. Proc. Natl. Acad. Sci. USA 96:4820.[Abstract/Free Full Text]
  22. Chandel, N. S., D. S. McClintock, C. E. Feliciano, T. M. Wood, J. A. Melendez, A. M. Rodriguez, P. T. Schumacker. 2000. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1{alpha} during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275:25130.[Abstract/Free Full Text]
  23. Kita, H.. 2002. Identification of HLA-A2-restricted CD8+ cytotoxic T cell responses in primary biliary cirrhosis: T cell activation is augmented by immune complexes cross-presented by dendritic cells. J. Exp. Med. 195:113.[Abstract/Free Full Text]
  24. Sasada, T., Y. Ghendler, J. M. Neveu, W. S. Lan, E. L. Reinherz. 2001. A naturally processed mitochondrial self-peptide in complex with thymic MHC molecules functions as a selecting ligand for a viral-specific T cell receptor. J. Exp. Med. 194:883.[Abstract/Free Full Text]
  25. Fliss, M. S., H. Usadel, O. L. Caballero, L. Wu, M. R. Buta, S. M. Eleff, J. Jen, D. Sidransky. 2000. Facile detection of mitochondrial DNA mutations in tumors and bodily fluids. Science 287:2017.[Abstract/Free Full Text]
  26. Pettit, S. J., K. Seymour, E. O’Flaherty, J. A. Kirby. 2000. Immune selection in neoplasia: towards a microevolutionary model of cancer development. Br. J. Cancer 82:1900.[Medline]
  27. Nagley, P., Y. H. Wei. 1998. Ageing and mammalian mitochondrial genetics. Trends Genet. 14:513.[Medline]
  28. Huang, C. N., S. H. Jee, J. J. Hwang, Y. F. Kuo, L. M. Chuang. 1998. Autoimmune IDDM in a sporadic MELAS patient with mitochondrial tRNA(Leu(UUR)) mutation. Clin. Endocrinol. (Oxf.) 49:265.[Medline]
  29. Ohkubo, K., A. Yamano, M. Nagashima, Y. Mori, K. Anzai, Y. Akehi, R. Nomiyama, T. Asano, A. Urae, J. Ono. 2001. Mitochondrial gene mutations in the tRNA(Leu(UUR)) region and diabetes: prevalence and clinical phenotypes in Japan. Clin. Chem. 47:1641.[Abstract/Free Full Text]
  30. Janssen, G. M., J. A. Maassen, J. M. van Den Ouweland. 1999. The diabetes-associated 3243 mutation in the mitochondrial tRNA(Leu(UUR)) gene causes severe mitochondrial dysfunction without a strong decrease in protein synthesis rate. J. Biol. Chem. 274:29744.[Abstract/Free Full Text]
  31. Serreze, D. V., E. H. Leiter, G. J. Christianson, D. Greiner, D. C. Roopenian. 1994. Major histocompatibility complex class I-deficient NOD-B2mnull mice are diabetes and insulitis resistant. Diabetes 43:505.[Abstract]




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