BACKGROUND: Mitochondria, which harbor their own genome (mtDNA), have attracted attention due to the potential of mtDNA copy number (mtDNA-CN) as an indicator of mitochondrial dysfunction. Although mtDNA-CN has been proposed as a simple and accessible biomarker for metabolic disorders such as metabolic dysfunction-associated steatotic liver disease, the underlying mechanisms and the causal relationship remain insufficiently elucidated. In this investigation, we combined longitudinal epidemiological data, animal studies, and in vitro assays to elucidate the potential causal relationship between reduced mtDNA-CN and the development of steatotic liver disease (SLD). METHODS: We conducted a longitudinal study using data from a health examination cohort initiated in 1981 in Yakumo, Hokkaido, Japan. Data from examinations performed in 2015 and 2022 were analyzed, focusing on 76 subjects without SLD at baseline (2015) to assess the association between baseline mtDNA-CN and subsequent risk of SLD development. In addition, 28-day-old SD rats were fed ad libitum on a 45% high-fat diet and dissected at 2 and 8 weeks of age. Blood and liver mtDNA-CN were measured and compared at each feeding period. Additionally, in vitro experiments were performed using HepG2 cells treated with mitochondrial function inhibitors to induce mtDNA-CN depletion and to examine its impact on intracellular lipid accumulation. RESULTS: Epidemiological analysis showed that the subjects with low mtDNA-CN had a significantly higher odds ratio for developing SLD compared to high (odds ratio [95% confidence interval]: 4.93 [1.08-22.50]). Analysis of the animal model showed that 8 weeks of high-fat diet led to the development of fatty liver and a significant decrease in mtDNA-CN. A further 2 weeks of high-fat diet consumption resulted in a significant decrease in hepatic mtDNA-CN, despite the absence of fatty liver development, and a similar trend was observed for blood. Complementary in vitro experiments revealed that pharmacologically induced mitochondrial dysfunction led to a significant reduction in mtDNA-CN and was associated with increases in intracellular lipid accumulation in HepG2 cells. CONCLUSIONS Our findings suggest that reduced mtDNA-CN may contribute causally to SLD development and could serve as a convenient, noninvasive biomarker for early detection and risk assessment.
Animals ; DNA, Mitochondrial/genetics* ; Humans ; Male ; DNA Copy Number Variations ; Female ; Fatty Liver/blood* ; Rats ; Middle Aged ; Longitudinal Studies ; Rats, Sprague-Dawley ; Adult ; Japan/epidemiology* ; Aged ; Biomarkers/blood* ; Hep G2 Cells ; Diet, High-Fat/adverse effects*

Background: and Purpose Carotid artery stenosis or occlusion (CASO) is a causative disease of vascular cognitive impairment (VCI) attributed to cerebral hypoperfusion, even without the development of symptomatic ischemic stroke. Preclinically, resveratrol has been demonstrated to play an important role in improving cognitive function in rodent CASO models. This study investigated the association between long-term resveratrol intake and improvements in cognitive and cerebral hemodynamic impairments in patients with CASO. Methods: A retrospective cohort study was conducted on patients with asymptomatic carotid artery stenosis of ≥50% or occlusion who underwent 15O-gas positron emission tomography (15O-gas PET) and neuropsychological tests such as Montreal Cognitive Assessment (MoCA) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 (ADAS-Cog) twice between July 2020 and March 2022 allowing >125-day interval. Patients were administered 30 mg/day resveratrol after the first 15O-gas PET and neuropsychological tests were compared with those who were not. Results: A total of 79 patients were enrolled in this study; 36 received resveratrol and 43 did not. Over a mean follow-up of 221.2 and 244.8 days, long-term resveratrol treatment significantly improved visuospatial/executive function (P=0.020) in MoCA, and memory domain (P=0.007) and total score (P=0.019) in ADAS-Cog. Cerebral blood flow demonstrated improvement in the right frontal lobe (P=0.027), left lenticular nucleus (P=0.009), right thalamus (P=0.035), and left thalamus (P=0.010) on 15O-gas PET. No adverse events were reported. Conclusion Long-term daily intake of oral resveratrol may prevent or treat VCI by improving the cerebral blood flow in asymptomatic patients with CASO.

Objective: The long-term efficacy of deep brain stimulation (DBS) for motor fluctuations in advanced Parkinson’s disease (PD) has been well established; however, motor fluctuations may recur over time despite multiple adjustments of DBS settings and medications. Methods: We conducted a retrospective chart review of three patients for whom levodopa-carbidopa intestinal gel (LCIG) was additionally administered as a rescue therapy for secondary DBS failure due to the recurrence of motor fluctuations. Results: The three patients had advanced PD with a disease duration of 14–19 years, and had undergone DBS for motor fluctuations refractory to standard medical management. LCIG was administered to the patients because of symptom recurrence years after DBS and provided complementary effects in all patients. Conclusion The cases presented here show that rescue LCIG therapy may be a complementary treatment option for patients with post-DBS advanced PD who have a recurrence of troublesome motor complications.

An investigation on the efficacy of preoperative autologous blood donation in open-heart surgery was made using frozen red blood cells and MAP red blood cells in cooperation with the Red Cross Blood Center. In 109 cases which received the donation, the rate of cases which received no homologous blood transfusion was 93.6% (35.3% in the cases without donation). Even in the cases of redo operation or aortic surgery, in which extensive blood loss is expected, 75% of those given a donation of 1600-2000ml frozen blood required no homologous blood transfusion. The hemoglobin concentration in the cases which received blood donation for more than 4 weeks did not decrease, indicating that safe donation is feasible. The aforementioned frozen and MAP blood preparations can be preserved for a long period so that blood donation can be started even before deciding on the date of operation. Also, its usefulness is not affected by the postponement of the operation. Furthermore, there was no problem in safety with respect to transfer, treatment, and storage of the autologous blood in cooperation with the Red Cross Blood Center, suggesting that this is useful as a preoperative donation method, especially in small- and middle-scale hospitals, which have no separate blood centers. However, there were 2 cases in which aggravated symptoms were noted after blood collection. Therefore, it is important to carefully select cases for autologous blood donation in open-heart surgery and it is desirable to set up appropriate donation schedules.