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A Pilot Study on the Effects of l-Carnitine and Trimethylamine-N-Oxide on Platelet Mitochondrial DNA Methylation and CVD Biomarkers in Aged Women.
Bordoni, L, Sawicka, AK, Szarmach, A, Winklewski, PJ, Olek, RA, Gabbianelli, R
International journal of molecular sciences. 2020;(3)
Abstract
l-carnitine supplementation has been used for cardiovascular health protection for a long time. Recently, trimethylamine-N-oxide (TMAO), which is an end product of l-carnitine metabolism via the activity of microbiota, has been identified as a cardiovascular disease (CVD) biomarker. The aim of this study was to assess the effect of 6 months of l-carnitine supplementation in a group of aged women engaged in a regular physical training. Platelet mitochondrial DNA methylation, an emerging and innovative biomarker, lipid profile and TMAO levels have been measured. TMAO increased after l-carnitine supplementation (before 344.3 ± 129.8 ng/mL vs. after 2216.8 ± 1869.0 ng/mL; n = 9; paired t-test, p = 0.02). No significant effects on TMAO were exerted by training alone (n = 9) or by l-leucine supplementation (n = 12). TMAO levels after 6 months of l-carnitine supplementation were associated with higher low-density lipoprotein-cholesterol (LDL-c) (Spearman Rho = 0.518, p = 0.003) and total cholesterol (TC) (Spearman Rho = 0.407, p = 0.026) levels. l-carnitine supplementation increased D-loop methylation in platelets (+6.63%; paired t-test, p = 0.005). D-loop methylation was not directly correlated to the TMAO augmentation observed in the supplemented group, but its increase inversely correlated with TC (Pearson coefficient = -0.529, p = 0.029) and LDL-c (Pearson coefficient = -0.439, p = 0.048). This evidence supports the hypothesis that the correlation between l-carnitine, TMAO and atherosclerosis might be more complex than already postulated, and the alteration of mitochondrial DNA (mtDNA) methylation in platelets could be involved in the pathogenesis of this multifactorial disease.
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Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.
Feuer, WJ, Schiffman, JC, Davis, JL, Porciatti, V, Gonzalez, P, Koilkonda, RD, Yuan, H, Lalwani, A, Lam, BL, Guy, J
Ophthalmology. 2016;(3):558-70
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Abstract
PURPOSE Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADHubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES Loss of visual acuity. RESULTS Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.
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Simultaneous quantification of mitochondrial DNA damage and copy number in circulating blood: a sensitive approach to systemic oxidative stress.
Chan, SW, Chevalier, S, Aprikian, A, Chen, JZ
BioMed research international. 2013;:157547
Abstract
Systemic oxidative stress is associated with a wide range of pathological conditions. Oxidative DNA damage is frequently measured in circulating lymphocytes. Mitochondrial DNA (mtDNA) is known to be more sensitive to oxidative damage than nuclear DNA but is rarely used for direct measurement of DNA damage in clinical studies. Based on the supercoiling-sensitive real-time PCR method, we propose a new approach for the noninvasive monitoring of systemic oxidative stress by quantifying the mtDNA structural damage and copy number change in isolated lymphocytes in a single test. We show that lymphocytes have significantly less mtDNA content and relatively lower baseline levels of damage than cancer cell lines. In an ex vivo challenge experiment, we demonstrate, for the first time, that exogenous H2O2 induces a significant increase in mtDNA damage in lymphocytes from healthy individuals, but no repair activity is observed after 1 h recovery. We further demonstrate that whole blood may serve as a convenient alternative to the isolated lymphocytes in mtDNA analysis. Thus, the blood analysis with the multiple mtDNA end-points proposed in the current study may provide a simple and sensitive test to interrogate the nature and extent of systemic oxidative stress for a broad spectrum of clinical investigations.
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Leber hereditary optic neuropathy gene therapy clinical trial recruitment: year 1.
Lam, BL, Feuer, WJ, Abukhalil, F, Porciatti, V, Hauswirth, WW, Guy, J
Archives of ophthalmology (Chicago, Ill. : 1960). 2010;(9):1129-35
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OBJECTIVE To describe the patient profiles of the Leber hereditary optic neuropathy (LHON) Gene Therapy Clinical Trial, year 1. This study aims to identify and characterize affected patients and carriers with the G11778A mutation in mitochondrial DNA for planned gene therapy that will use "allotopic expression" by delivering a normal nuclear-encoded ND4 gene into the nuclei of retinal ganglion cells via an adeno-associated virus vector injected into the vitreous. METHODS Patients with LHON with visual loss as well as asymptomatic maternally related family members were molecularly screened for ND1, ND4, and ND6 mutations in mitochondrial DNA commonly associated with LHON. All patients and maternal relatives also underwent complete neuro-ophthalmic examination, automated visual field testing, pattern electroretinogram (PERG), and OCT3. RESULTS Twenty-five subjects with LHON and 21 carriers positive for the G11778A mitochondrial DNA mutation were recruited. Three additional mutations in the ND4 gene, G11719A, G11947A, or G11914A, were detected. Mean retinal nerve fiber layer (RNFL) thickness was 78.3 μm up to 32 months after visual loss. It was 63.5 μm for all affected patients and 100.7 μm for carriers (P < .01). Mean PERG amplitude was lower in affected patients (40% of normal) than in carriers (94% of normal) (P < .01). Four carriers with PERG amplitudes less than 75% of normal had Early Treatment Diabetic Retinopathy Study acuity more than 20/25, mean defect more than -2 dB, and average RNFL thickness more than 80 μm. CONCLUSIONS Potential candidates for future gene therapy may include affected patients, as late as 32 months after loss of vision, with mildly reduced RNFL thickness or carriers with low PERG amplitudes and normal RNFL thickness, if the PERG amplitude is a predictor of conversion to LHON in these carriers.
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Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: a randomized, double-blind, placebo-controlled pilot study.
Rabing Christensen, E, Stegger, M, Jensen-Fangel, S, Laursen, AL, Ostergaard, L
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2004;(9):1371-9
Abstract
BACKGROUND Mitochondrial toxicity can be induced by reverse-transcriptase inhibitors, and an association between levels of mitochondrial DNA (mtDNA) per cell and lipodystrophy, peripheral neuropathy, and HIV infection per se has been suggested. Studies aimed at increasing the oxidative capacity in HIV-infected patients have been sparse. METHODS Levels of mtDNA in fat and peripheral blood mononuclear cells (PBMCs) from 25 HIV infected patients and 10 healthy control subjects were studied with real-time PCR analysis. A placebo-controlled and double-blind design was used to assign individuals to receive either 100 mg of coenzyme Q twice daily for 3 months or a matching placebo regimen. Levels of mtDNA and other parameters were assessed before and after the intervention period. RESULTS The mean number of mtDNA copies per cell was lower in fat tissue obtained from patients with peripheral neuropathy (1547 mtDNA copies/cell; P=.045), patients with lipodystrophy (1732 mtDNA copies/cell; P=.003) and in HIV patients with no complications associated with highly active antiretroviral therapy (2935 mtDNA copies/cell; P=.078), compared with healthy control subjects (6198 mtDNA copies/cell). No clear difference was seen in mtDNA content in PBMCs. Coenzyme Q therapy improved the general condition of patients (P=.005) and caused a reversible increase in peripheral neuropathy pain (P=.048). Compared with placebo, treatment with coenzyme Q did not result in changes in mtDNA levels in fat cells or in PBMCs after the treatment period. CONCLUSIONS Levels of mtDNA in fat tissue, but not in PBMCs, were associated with peripheral neuropathy and lipodystrophy. High-dose coenzyme Q therapy increased well-being in asymptomatic HIV-infected patients and those with lipodystrophy, as well as in control subjects, but aggravated pain in patients with peripheral neuropathy.
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[Effect of wuzi yanzong Pill on mitochondrial DNA deletion and respiratory chain enzyme complex activity in peripheral leukocyte of aged male with kidney deficiency syndrome].
Wang, XM, Fu, H, Liu, GX
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2002;(2):101-3
Abstract
OBJECTIVE To investigate the effect of Wuzi Yanzong Pill (WZYZP) on mitochondrial DNA (mtDNA) deletion and respiratory chain enzyme complex (RCZC) in peripheral blood leukocyte of aged male with Kidney Deficiency Syndrome (KDS). METHODS Single-blinded study was conducted in 38 aged male with KDS, who were randomly divided into 2 groups treated with WZYZP and placebo respectively for 3 months. Levels of mtDNA deletion and RCZC were determined by polymerase chain reaction (PCR) and enzyme kinetics technique respectively. RESULTS WZYZP could reduce the mtDNA deletion and raise the activity of mitochondrial RCZC I, IV in peripheral blood leukocyte of aged male with KDS (P < 0.05, P < 0.01). CONCLUSION WZYZP has protective effect on mtDNA from oxidative damage in leukocyte of aged male with KDS.
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Ubiquinone and nicotinamide treatment of patients with the 3243A-->G mtDNA mutation.
Remes, AM, Liimatta, EV, Winqvist, S, Tolonen, U, Ranua, JA, Reinikainen, K, Hassinen, IE, Majamaa, K
Neurology. 2002;(8):1275-7
Abstract
The efficacy and safety of ubiquinone (Q10) and nicotinamide were evaluated in a 6-month open-label trial in patients with the 3243A-->G mitochondrial DNA mutation. Blood lactate and pyruvate concentrations decreased, but there was little clinical improvement. Q10 and nicotinamide were well tolerated, but two patients died suddenly and unexpectedly during the trial. These deaths may have been unrelated to treatment. The unpredictable course of the disease makes evaluation of the clinical response difficult.
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Effect of exercise on the mitochondrial DNA content of peripheral blood in healthy women.
Lim, S, Kim, SK, Park, KS, Kim, SY, Cho, BY, Yim, MJ, Lee, HK
European journal of applied physiology. 2000;(5-6):407-12
Abstract
Exercise decreases insulin resistance and increases maximal exercise capacity as estimated from maximal oxygen uptake (VO2max). Recent reports have demonstrated that the mitochondrial DNA (mtDNA) content of blood is correlated with VO2max in healthy subjects (mean age 31 years) and is inversely correlated with insulin resistance parameters. The aim of this study was to determine the effect of regular exercise on the mtDNA content in the peripheral blood of 16 healthy young women of mean age 24.8 (SD 6.2) years and 14 healthy older women of mean age 66.7 (SD 5.8) years. The exercise programme lasted for 10 weeks and consisted of three sessions a week, each of 1 h and aiming to attain 60%-80% of VO2max. The mtDNA content of peripheral blood was measured by competitive polymerase chain reaction. The VO2max had significantly increased following the exercise programme [from 33.1 (SD 3.4) to 35.2 (SD 3.4) ml x kg(-1) min(-1) in the young and from 24.3 (SD 5.3) to 30.3 (SD 7.3) ml x kg(-1) x min(-1) in the older women, both P < 0.05]. Exercise decreased systolic blood pressure, and concentrations of triglyceride, low density lipoprotein-cholesterol (LDL-C), glucose and insulin in the blood of the young and of total cholesterol, LDL-C and glucose in that of the older women. High density lipoprotein-cholesterol (HDL-C) in the young women was increased by exercise. The mtDNA content significantly increased following the exercise programme in both groups [from 27.1 (SD 17.9) to 52.7 (SD 44.6) amol x 5 ng(-1) genomic DNA in the young and from 15.3 (SD 10.2) to 32.1 (SD 30.0) amol x 5 ng(-1) genomic DNA in the older women, both P < 0.05]. There was a significant positive correlation between the change in mtDNA content and the change in VO2max (r = 0.74 in the young and r = 0.71 in the older women, both P < 0.01). In conclusion, 10 weeks of moderate intensity, regular exercise increased the mtDNA content in peripheral blood and decreased insulin resistance parameters. This data suggests that increase in the mtDNA content may be associated with increased insulin sensitivity.