|
 |
|
|||||||
|
|||||||||
© 2003 by the American Diabetes Association, Inc.
Letters: Observations |
Multiple Tumors in Mitochondrial Diabetes Associated With tRNALeu(UUR) Mutation at Position 3264
1 Saiseikai Central Hospital, Tokyo, Japan
2 Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
3 Fujigaoka Hospital, Showa University, Kanagawa, Japan
4 Department of Neuropsychiatry, Keio University, Tokyo, Japan
5 Department of Biochemistry and Cell Biology, Institute of Gerontology, Nippon Medical School, Kanagawa, Japan
In 1997, we reported the first identified case of mitochondrial diabetes caused by a T-to-C transition at position 3264 (1). The proband was a 64-year-old man. His family tree revealed maternally inherited diabetes. He had diabetes, cerebellar ataxia, hearing loss, olfactory dysfunction, bilateral facial nerve palsy, oculomotor palsy, and cervical lipoma. Heteroplasmy of the 3264 mutation, maternal inheritance of diabetes, absence of 3264 mutation in control subjects, and symptoms related to mitochondrial dysfunction suggested that this 3264 mutation was pathogenic.
During a 6-year follow-up period, he developed left-sided hearing loss and had an acoustic neuroma at age 68 years (13 mm x 15 mm). He died at age 70 years of hepatic failure due to hepatocellular carcinoma. Hence, during his lifetime, this patient experienced multiple tumors (gastric cancer, hepatocellular carcinoma, benign lipoma, and acoustic neuroma). Furthermore, it is noteworthy that his five brothers and sisters, who died after age 30 years, all died of malignancies, i.e., gastric cancer, hepatocellular carcinoma, prostate cancer, and laryngeal cancer.
Evidence has recently accumulated indicating that mitochondrial abnormalities may play important roles in tumorigenesis. Amuthan et al. (2) suggested a new pathway by which mitochondrial DNA and membrane damage may contribute to tumor progression and metastasis. Fumarate hydratase and succinate dehydrogenase are mitochondrial enzymes functioning in the tricarboxylic acid cycle. Mutations of these enzymes reportedly cause leiomyomatosis and hereditary paragangliomas, respectively (3,4). Because mitochondria are key organelles in the induction of oxidative stress and control of apoptosis (5,6), and because the development of four types of tumors in an individual with a rare mitochondrial disorder is unlikely to be a coincidence, we speculate that mitochondrial dysfunction due to the 3264 mtDNA mutation might have induced oxidative stress associated with tumorigenesis, or render tumor cells susceptible to disordered caspase cascades, in our patient.
In conclusion, although a single case study is insufficient to determine pathogenesis, the present case does suggest associations among mitochondrial dysfunction, diabetes, and tumorigenesis.
Acknowledgments
The authors would like to thank Prof. Souroku Yagihashi for valuable advice and for critical reading of the manuscript.
Footnotes
Address correspondence to Dr. Yoshihiko Suzuki. 1-4-17, Diabetes Department, Saiseikai Central Hospital, Mita, Mitano-Ku, Tokyo. E-mail: drsuzuki{at}cts.ne.jp.
References
- Suzuki Y, Suzuki S, Hinokio Y, Chiba M, Atsumi Y, Hosokawa K, A Shimada A, Asahina T, Matsuoka K: Diabetes associated with a novel 3264 mitochondrial tRNALeu(UUR) mutation. Diabetes Care 20: 1138–1140, 1997[Abstract]
- Amuthan G, Biswas G, Zhang SY, Klein-Szanto A, Vijayasarathy C, Avadhani NG: Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J 20: 1910–1920, 2001[Medline]
- Baysal BE, Ferrel RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, Mey A, Taschner PEM, Rubinstein WS, Myers EN, Richard CW, Cornelisse CJ, Devilee P, Devlin B: Mutations in SDHD, a mitochondrial complex 2 gene, in hereditary paraganglioma. Science 287: 848–851, 2000
[Abstract/Free Full Text]
- The Mutiple Leiomyoma Consortium: Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet 30: 406–410, 2002[Medline]
- Kamat JP, Devasagayam TP: Oxidative damage to mitochondria in normal and cancer tissues, and its modulation. Toxicology 155: 73–82, 2000[Medline]
- Rustin P: Mitochondria, from cell death to proliferation. Nat Genet 30: 352–353, 2002[Medline]
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |