As mitochondria play a major role in the conversion of dietary calories into usable energy, generating reactive oxygen species as a toxic byproduct, mitochondrial dysfunction plays a role in a wide range of age-related disorders and various forms of cancer. The present report concerns a heavy smoker who died of lung cancer at age 40. He also developed progressive diabetes and sensory hearing loss. Mitochondrial DNA sequence analysis revealed four mutations in peripheral mononuclear cells. Three were novel point mutations, including a mutation in ATP synthase F0 subunit 6 (ATP6). Mitochondrial mutations and smoking may have contributed to the development of atypical early onset of senescence-related diseases in this case.
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This case suggests that novel mitochondrial mutations are associated with the early development of senescence-related diseases, such as diabetes, hearing loss and cancer.1
The subject was well until a diagnosis of diabetes mellitus was made during routine health screening in his early 20s. Although diet therapy was initiated, his diabetic control showed gradual deterioration. Sulfonylurea was started after 2 years. His bilateral hearing ability became gradually impaired and use of an artificial hearing device was initiated in his early 30s. After starting insulin injection 5 years later, his diabetes was moderately controlled. His plasma HbA1c increased abruptly with body weight loss after a further 5 years. He was admitted to our inpatient clinic to evaluate the causes of deteriorated diabetic control. His father was healthy and still alive. Information for his mother was not available. He was a heavy smoker. His Blinkman index was 440. On physical examination at the time of admission, he was emaciated and with a body mass index (BMI) of 12 kg/m2. There were no other remarkable findings, including optic atrophy, except obvious right hemianopsia. Blood chemistry analysis indicated hypoproteinaemia, hypoalbuminaemia with acute inflammation reflected by leukocytosis with positive C-reactive protein. His HbA1c was 8.9% and urinary C-peptide immunoreactivity was 8.5 μg per day. The tumour markers studied were normal, but chest x ray showed shadows in the lower right lung field. Brain and lung CT revealed a mass 4 cm in diameter in the right lung and a mass 2 cm in diameter in the occipital region of the brain, respectively (fig 1A,B). An audiogram showed moderate sensory hearing disturbance at all wavelengths tested (fig 1C). Bronchoscopic biopsy demonstrated non-small cell lung cancer. No interventional chemotherapy was indicated because of the patient’s severe emaciation, and he died due to respiratory insufficiency 2 months after admission.
Poorly differentiated adenocarcinoma of the lung was found on autopsy (fig 1D). Brain metastasis and lung emphysema were present. No fibrosis, no lymphoinfiltration and no amyloid deposition were observed with low numbers of β cells in the pancreas (fig 1E). Cardiomyopathy was not present. No evidence of haematological malignancy was indicated. His genomic DNA was extracted from the specimen obtained at the time of admission. All mitochondrial genomic DNA were sequenced with the approval of the Shinshu University Ethical Committee. As shown in fig 2, four abnormalities were detected in his mitochondrial genes in the peripheral leukocytes. First, there was a mutation in the NADH dehydrogenase subunit 2 gene although the amino acid sequence was not altered (fig 2A). The second was a G to T transversion at nucleotide 8304 in the gene encoding lysine transfer RNA (fig 2B). The third was G to A transition at nucleotide 8572 (fig 2C), which is in the coding regions of two genes. The first was the terminal codon of ATP synthase F0 subunit 8, in which the sequence TAG was changed to TAA, resulting in no alteration in the final message. This mutation, however, also resulted in a glycine to serine change at the 16th amino acid of ATP synthase F0 subunit 6. The last genetic finding was a T to C point mutation at nucleotide 16 189 in the D-loop with a 3-base or 5-base insertion of C observed adjacent to the point mutation in the D-loop, indicating heteroplasmy in mitochondrial DNA in this patient (fig 2D). According to Mitomap (http://www.mitomap.org/), with the exception of the last heteroplasmic sequence region, none of these mutations had been reported previously. Sequence analysis was performed with the DNA extracted from paraffin-embedded sections of his lung cancer, pancreas and heart tissue. There was no evidence of any of the above mutations in the tissues studied.
Many of the disorders associated with mitochondrial dysfunction cause diabetes, hearing loss and malignant tumours. Although the patient’s family history and precise medical history in the initial development of diabetes were not available, the onset at a young age and no history of obesity with gradual but progressive impairment of insulin secretion in this case suggested that the development of diabetes may have been caused, at least in part, by congenital rather than acquired factors. Patients with mitochondrial mutations develop sensorineural and progressive hearing loss, mainly affecting the high frequencies in the initial stage and gradually affecting lower frequencies with increasing age. These observations indicate that the impaired wavelengths are age dependent but the bilateral sensory and progressive features are common in mitochondrial hearing loss, as shown in this case.2,3 Although the extent to which cancer is caused by or is a consequence of mitochondrial genomic alterations is unknown, lung cancers with mitochondrial abnormalities have been reported.4 Lack of findings such as fibrosis or lymphoinfiltration in the pancreas suggests that chronic pancreatitis or autoimmune-mediated insulitis may not have been responsible for the diabetes in the present case. As amyloid deposition is typical in patients with type 2 diabetes mellitus, the lack of amyloid deposition and reduced number of β cells indicated a relative lack of insulin rather than hypersecretion in this case. In contrast to the apparent heteroplasmy observed in the D-loop region, the three mutations were homoplasmic in peripheral mononuclear cells. The mutations in the D-loop in this case have been reported as polymorphic variations in normal subjects.5 By contrast, each homoplasmic mutation was novel. The development of three homoplasmic mutations may occur via different molecular mechanisms from the heteroplasmic mutations in the D-loop. Mutation 8344 in lysine transfer RNA was reported to be associated with diabetic patients in whom insulin secretory capacity is low.6 Although the nucleotide position was different, abnormal transfer RNA may have been related to the progressive diabetes in the present case. The mitochondrial gene ATP6 contributes to ATP synthesis by transporting protons from the intermembrane space into the matrix in mitochondria.7 This protein controls mitochondrial oxidative phosphorylation. Mutations in the gene have been reported in patients with the Leber hereditary optic neuropathy (LHON).8 It is not surprising that the abnormal ATP synthase may affect mitochondrial ATP synthesis and reactive oxygen pathways may result in progression of the development of diabetes, hearing loss and lung cancer. The development of lung cancer may be associated with heavy smoking in addition to mitochondrial dysfunction.9 All mutations were found in peripheral mononuclear cells, but not in somatic tissues, indicating that mutations may have been limited in peripheral mononuclear cells at the time of admission. The amount of abnormal mitochondrial genome is known to vary among the different tissues and periods of life.10 The precise tissue-specific expression of mitochondrial mutations has not been clarified, but the abnormal mitochondrial function may have interacted in the development of diabetes, hearing loss and lung cancer in this case.
In conclusion, we present the case of a male patient who developed diabetes, hearing loss and cancer. The pathological findings and mutations in mitochondrial DNA were described. The findings in this case suggest that genetic factors in mitochondria are important for the development of senescence-related diseases in addition to acquired factors, such as smoking. Familial analyses were not available for this case. The precise relationships between the series of mutations and early onset of diabetes, hearing loss and lung cancer remain to be elucidated.
Diabetes, hearing loss and cancer may have been related to mitochondrial mutations in this case.
Although the mutations were revealed only in the peripheral leukocytes, three mutations were novel and one affected mitochondrial function.
Genetic factors in mitochondria are important for the development of senescence-related diseases in addition to acquired factors, such as smoking.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.