Increased mitochondrial DNA deletions and copy number in transfusion-dependent thalassemia

Abstract

BACKGROUND Iron overload is the primary cause of morbidity in transfusion-dependent thalassemia. Increase in iron causes mitochondrial dysfunction under experimental conditions, but the occurrence and significance of mitochondrial damage is not understood in patients with thalassemia. METHODS Mitochondrial DNA (mtDNA) to nuclear DNA copy number (Mt/N) and frequency of the common 4977-bp mitochondrial deletion (ΔmtDNA4977) were quantified using a quantitative PCR assay on whole blood samples from 38 subjects with thalassemia who were receiving regular transfusions. RESULTS Compared with healthy controls, Mt/N and ΔmtDNA4977 frequency were elevated in thalassemia (P = 0.038 and P < 0.001, respectively). ΔmtDNA4977 was increased in the presence of either liver iron concentration > 15 mg/g dry-weight or splenectomy, with the highest levels observed in subjects who had both risk factors (P = 0.003). Myocardial iron (MRI T2* < 20 ms) was present in 0%, 22%, and 46% of subjects with ΔmtDNA4977 frequency < 20, 20–40, and > 40/1 × 107 mtDNA, respectively (P = 0.025). Subjects with Mt/N values below the group median had significantly lower Matsuda insulin sensitivity index (5.76 ± 0.53) compared with the high Mt/N group (9.11 ± 0.95, P = 0.008). CONCLUSION Individuals with transfusion-dependent thalassemia demonstrate age-related increase in mtDNA damage in leukocytes. These changes are markedly amplified by splenectomy and are associated with extrahepatic iron deposition. Elevated mtDNA damage in blood cells may predict the risk of iron-associated organ damage in thalassemia.

Identification of Circulating Endocan-1 and Ether Phospholipids as Biomarkers for Complications in Thalassemia Patients

“…Our findings, and previous studies, regarding TGs, sphingomyelins, and acylcarnitines, convey the important metabolic perturbations that occur in thalassemia patients [17,[36][37][38][39] and also extend our knowledge about their relationship to clinical parameters. Glycerolipids are the lipid class that were most affected in thalassemia patients, representing about 50% of all lipid species of the observed lipidomic signature, of which 90% were TGs.…”

“…Ether lipids have been the subject of several recent reviews [37,45], potentially relevant in thalassemia due to (i) antioxidant properties due to the presence of the vinyl ether bond in alkenyls, (ii) polyunsaturated fatty acid (PUFA) source, and (iii) immune cell viability. Numerous studies have reported low circulating ether phospholipids or plasmalogens in patients with diseases associated with mitochondrial or peroxisome dysfunction [24,38,46] or leukocyte mitochondrial damage [39]. A lower level of circulating plasmalogens, namely ether PC or PEs, has not been previously reported in thalassemia patients.…”

Toxic myopathy with multiple deletions in mitochondrial DNA associated with long‐term use of oral anti‐viral drugs for hepatitis B: A case study

“…Because the patient had no muscle weakness or cerebellar ataxia until 4 months prior to admission, it was unlikely she had a congenital mtDNA deletion. The mtDNA CD is a marker of mtDNA damage and its incidence increases with age and oxidative stress . We suggest that the CD in the present case was caused not only by aging but also by other factors because the CD incidence in the patient's skeletal muscle was higher than that in people over 70 years of age (0.23% vs. 0.06%, respectively) .…”

“…The mtDNA CD is a marker of mtDNA damage and its incidence increases with age and oxidative stress. [10][11][12] We suggest that the CD in the present case was caused not only by aging but also by other factors because the CD incidence in the patient's skeletal muscle was higher than that in people over 70 years of age (0.23% vs. 0.06%, respectively). 10 It is conceivable that longterm intake of lamivudine and adefovir is one of the causative factors.…”

The effect of splenectomy on complement regulatory proteins in erythrocytes in β-thalassemia major

“…They found that erythrocyte PS exposure was significantly higher in splenectomized β-TM patients compared with nonsplenectomized β-TM patients [21]. Lal et al reported that splenectomy and iron overload have an additive effect on increasing the frequency of mitochondrial DNA deletions (ΔmtDNA 497 ) in β-Thal patients [22]. Splenectomy results in damage to both the erythrocyte membrane and mitochondrial DNA as shown in these studies.…”