Mitochondrial DNA with a Large-Scale Deletion Causes Two Distinct Mitochondrial Disease Phenotypes in Mice

Studies in patients have suggested that the clinical phenotypes of some mitochondrial diseases might transit from one disease to another (e.g., Pearson syndrome [PS] to Kearns-Sayre syndrome) in single individuals carrying mitochondrial (mt) DNA with a common deletion (∆mtDNA), but there is no direct experimental evidence for this. To determine whether ∆mtDNA has the pathologic potential to induce multiple mitochondrial disease phenotypes, we used trans-mitochondrial mice with a heteroplasmic state of wild-type mtDNA and ∆mtDNA (mito-mice∆). Late-stage embryos carrying ≥50% ∆mtDNA showed abnormal hematopoiesis and iron metabolism in livers that were partly similar to PS (PS-like phenotypes), although they did not express sideroblastic anemia that is a typical symptom of PS. More than half of the neonates with PS-like phenotypes died by 1 month after birth, whereas the rest showed a decrease of ∆mtDNA load in the affected tissues, peripheral blood and liver, and they recovered from PS-like phenotypes. The proportion of ∆mtDNA in various tissues of the surviving mito-mice∆ increased with time, and Kearns-Sayre syndrome−like phenotypes were expressed when the proportion of ∆mtDNA in various tissues reached >70–80%. Our model mouse study clearly showed that a single ∆mtDNA was responsible for at least two distinct disease phenotypes at different ages and suggested that the level and dynamics of ∆mtDNA load in affected tissues would be important for the onset and transition of mitochondrial disease phenotypes in mice

Effects of Chlorogenic Acid-Enriched and Hydroxyhydroquinone-Reduced Coffee on Postprandial Fat Oxidation and Antioxidative Capacity in Healthy Men: A Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Chlorogenic acids (CGAs) reduce blood pressure and body fat, and enhance fat metabolism. In roasted coffee, CGAs exist together with the oxidant component hydroxyhydroquinone (HHQ). HHQ counteracts the antihypertensive effects of CGA, but its effects on CGA-induced fat oxidation (FOX) are unknown. Here we assessed the effects of CGA-enriched and HHQ-reduced coffee on FOX. Fifteen healthy male volunteers (age: 38 ± 8 years (mean ± SD); BMI: 22.4 ± 1.5 kg/m2) participated in this crossover study. Subjects consumed the test beverage (coffee) containing the same amount of CGA with HHQ (CGA-HHQ(+)) or without HHQ (CGA-HHQ(−)) for four weeks. Postprandial FOX and the ratio of the biological antioxidant potential (BAP) to the derivatives of reactive oxygen metabolites (d-ROMs) as an indicator of oxidative stress were assessed. After the four-week intervention, postprandial FOX and the postprandial BAP/d-ROMs ratio were significantly higher in the CGA-HHQ(−) group compared with the CGA-HHQ(+) group (4 ± 23 mg/min, group effect: p = 0.040; 0.27 ± 0.74, group effect: p = 0.007, respectively). In conclusion, reducing the amount of HHQ facilitated the postprandial FOX effects of CGA in coffee. Our findings also suggest that the mechanism underlying the inhibition of FOX by HHQ is related to postprandial oxidative stress

Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data

<p><b>Objectives:</b> There is scarce evidence comparing novel oral anticoagulants (NOACs) with warfarin in real-world settings in Japan. This study compared the risk of bleeding events among patients with non-valvular atrial fibrillation (NVAF) initiating treatment with NOACs versus warfarin.</p> <p><b>Methods:</b> A retrospective cohort study was conducted using a de-identified electronic health record based database of health claims and Diagnosis Procedure Combination data from 275 consenting hospitals in Japan. NVAF patients newly initiated on oral anticoagulants were eligible. Based on the first prescription, patients were assigned to 5/2.5 mg BID apixaban, 150/110 mg BID dabigatran, 15/10 mg QD rivaroxaban (approved dose lower in Japan compared to Western countries [20/15 mg QD]) or warfarin groups. One-to-one propensity score matching (PSM) was used to balance patient characteristics between warfarin and each NOAC. Patients were followed up to 1 year post-first prescription.</p> <p><b>Results:</b> Among 38,662 eligible patients, a total of 5977, 5090, and 6726 matched pairs were identified for warfarin versus apixaban, warfarin versus dabigatran, and warfarin versus rivaroxaban, respectively after PSM. Compared to warfarin, apixaban (hazard ratio [HR] 0.586; 95% CI 0.421–0.815), dabigatran (HR 0.617; 0.425–0.895) and rivaroxaban (HR 0.693; 0.514–0.933) were associated with a significantly lower risk of major bleeding. The risk of any bleeding was significantly lower for apixaban (HR 0.782; 0.682–0.896), but not for dabigatran (HR 0.988; 0.860–1.135) or rivaroxaban (HR 0.938; 0.832–1.057) when comparing to warfarin.</p> <p><b>Conclusions:</b> Among Japanese patients with NVAF, treatment with apixaban 5/2.5 mg BID was associated with a significantly lower risk of major bleeding and any bleeding when compared to warfarin. Treatment with dabigatran 150/110 mg BID or rivaroxaban 15/10 mg QD was associated with a significantly lower risk of major bleeding, but not any bleeding, than warfarin. The potential benefit of individual NOACs in real-world practice needs to be assessed further.</p

Mitochondrial DNA Mutations in Mutator Mice Confer Respiration Defects and B-Cell Lymphoma Development

<div><p>Mitochondrial DNA (mtDNA) mutator mice are proposed to express premature aging phenotypes including kyphosis and hair loss (alopecia) due to their carrying a nuclear-encoded mtDNA polymerase with a defective proofreading function, which causes accelerated accumulation of random mutations in mtDNA, resulting in expression of respiration defects. On the contrary, transmitochondrial mito-miceΔ carrying mtDNA with a large-scale deletion mutation (ΔmtDNA) also express respiration defects, but not express premature aging phenotypes. Here, we resolved this discrepancy by generating mtDNA mutator mice sharing the same C57BL/6J (B6J) nuclear background with that of mito-miceΔ. Expression patterns of premature aging phenotypes are very close, when we compared between homozygous mtDNA mutator mice carrying a B6J nuclear background and selected mito-miceΔ only carrying predominant amounts of ΔmtDNA, in their expression of significant respiration defects, kyphosis, and a short lifespan, but not the alopecia. Therefore, the apparent discrepancy in the presence and absence of premature aging phenotypes in mtDNA mutator mice and mito-miceΔ, respectively, is partly the result of differences in the nuclear background of mtDNA mutator mice and of the broad range of ΔmtDNA proportions of mito-miceΔ used in previous studies. We also provided direct evidence that mtDNA abnormalities in homozygous mtDNA mutator mice are responsible for respiration defects by demonstrating the co-transfer of mtDNA and respiration defects from mtDNA mutator mice into mtDNA-less (ρ⁰) mouse cells. Moreover, heterozygous mtDNA mutator mice had a normal lifespan, but frequently developed B-cell lymphoma, suggesting that the mtDNA abnormalities in heterozygous mutator mice are not sufficient to induce a short lifespan and aging phenotypes, but are able to contribute to the B-cell lymphoma development during their prolonged lifespan.</p> </div