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 × 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.
Article Information
The authors would like to thank Prof. Souroku Yagihashi for valuable advice and for critical reading of the manuscript.
References
Address correspondence to Dr. Yoshihiko Suzuki. 1-4-17, Diabetes Department, Saiseikai Central Hospital, Mita, Mitano-Ku, Tokyo. E-mail: [email protected].
