Nicotinamide adenine dinucleotide（NADH） in its reduced form of is a key coenzyme in redox reactions, essential for maintaining energy homeostasis.NADH and its oxidized counterpart, NAD+, form a redox couple that regulates various biological processes, including calcium homeostasis, synaptic plasticity, anti-apoptosis, and gene expression. The reduction of NAD+/NADH levels is closely linked to mitochondrial dysfunction, which plays a pivotal role in the cascade of various neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease.Auditory neuropathy（AN） is recognized as a clinical biomarker in neurodegenerative disorders. Furthermore, mitochondrial dysfunction has been identified in patients with mutations in genes like OPA1and AIFM1. However, effective treatments for these conditions are still lacking. Increasing evidence suggests that administratering NAD+ or its precursors endogenously may potentially prevent and slow disease progression by enhancing DNA repair and improving mitochondrial function. Therefore, this review concentrates on the metabolic pathways of NAD+/NADH production and their biological functions, and delves into the therapeutic potential and mechanisms of NADH in treating AN.
Humans ; NAD/metabolism* ; Neurodegenerative Diseases/metabolism* ; Mitochondria ; Oxidation-Reduction ; Mitochondrial Diseases

Humans ; Mitochondrial Diseases/prevention & control* ; DNA, Mitochondrial/genetics*

To evaluate e-cigarette vaping-induced respiratory toxicity and the interventional effects of air cleaners. A randomized controlled trial study of toxic vaping by the respiratory tract were conducted at the Key Laboratory of Environmental Medical Engineering, Ministry of Education, the School of Public Health, Southeast University from January to December 2022. 8-week-old male C57BL/6JGpt mice selected with a random number table method were used to establish a vaping-exposure model at different periods (0 d, 3 d, 7 d or 14 d), or exposed to clean air as a control group. Mice were exposed to regular heated vaping (200 ℃) and high-temperature heated vaping (280 ℃). Total lung RNA was extracted from control and e-cigarette exposed mice for transcriptome sequencing analysis. Reactive Oxygen Species (ROS) generation and mitochondrial membrane potential (MMP) were detected by flow cytometry. Total superoxide dismutase (SOD) and superoxide (O^2-) were evaluated using a microplate reader. Real-Time Quantitative PCR (RT-qPCR) was used to detect gene expression. Air filter and ionizer were used to intervene the toxicity of vaping. Data were expressed as (x¯±s), differences between multiple groups were compared using one-way or two-way ANOVA. The results showed that, RNA sequencing assays suggested that the differential genes between the control and vaping exposure groups were significantly enriched in the oxidative stress (Fold Enrichment=3.18) and mitochondrial oxidative phosphorylation (OXPHOS) (Fold Enrichment=5.74) pathways. Both types of heated vaping exposure caused significantly increased the score of alveolitis (F=10.8, P<0.001), increased endogenous ROS generation (F=16.8, P<0.001), decreased MMP (F=13.6, P<0.01), and gene expression of mitochondrial complex I dysfunction. The toxic effects of high-temperature heated vaping were stronger compared to regular heated vaping (F=2.9, P<0.05). The filter demonstrated better protective effects against vaping than the ionizer by reducing pulmonary alveolitis (F=7.4, P<0.01). Air cleaners could partially alleviate oxidative stress and mitochondrial dysfunction. In conclusion, this study demonstrate that vaping brings potential health risks. Air cleaners could partially reverse mitochondrial dysfunction, but cannot completely prevent the toxic effects, effective interventions remain to be investigated.
Humans ; Male ; Animals ; Mice ; Mice, Inbred C57BL ; Electronic Nicotine Delivery Systems ; Reactive Oxygen Species ; Vaping ; Mitochondrial Diseases

Humans ; Mitochondrial Diseases/therapy* ; DNA, Mitochondrial/genetics*

Objective: To investigate the clinical features and genetic features of combined oxidative phosphorylation deficiency 32 (COXPD32) caused by MRPS34 gene variation. Methods: The clinical data and genetic test of a child with COXPD32 hospitalized in the Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in March 2021 were extracted and analyzed. A literature search was implemented using Wanfang, China biology medicine disc, China national knowledge infrastructure, ClinVar, human gene mutation database (HGMD) and Pubmed databases with the key words "MRPS34" "MRPS34 gene" and "combined oxidative phosphorylation deficiency 32" (up to February 2023). Clinical and genetic features of COXPD32 were summarized. Results: A boy aged 1 year and 9 months was admitted due to developmental delay. He showed mental and motor retardation, and was below the 3^rd percentile for height, weight, and head circumference of children of the same age and gender. He had poor eye contact, esotropia, flat nasal bridge, limbs hypotonia, holding instability and tremors. In addition, Grade Ⅲ/6 systolic murmur were heard at left sternal border. Arterial blood gases suggested that severe metabolic acidosis with lactic acidosis. Brain magnetic resonance imaging (MRI) showed multiple symmetrical abnormal signals in the bilateral thalamus, midbrain, pons and medulla oblongata. Echocardiography showed atrial septal defect. Genetic testing identified the patient as a compound heterozygous variation of MRPS34 gene, c.580C>T (p.Gln194Ter) and c.94C>T (p.Gln32Ter), with c.580C>T being the first report and a diagnosis of COXPD32. His parents carried a heterozygous variant, respectively. The child improved after treatment with energy support, acidosis correction, and "cocktail" therapy (vitaminB₁, vitaminB₂, vitaminB₆, vitaminC and coenzyme Q10). A total of 8 cases with COXPD32 were collected through 2 English literature reviews and this study. Among the 8 patients, 7 cases had onset during infancy and 1 was unknown, all had developmental delay or regression, 7 cases had feeding difficulty or dysphagia, followed by dystonia, lactic acidosis, ocular symptoms, microcephaly, constipation and dysmorphic facies(mild coarsening of facial features, small forehead, anterior hairline extending onto forehead,high and narrow palate, thick gums, short columella, and synophrys), 2 cases died of respiratory and circulatory failure, and 6 were still alive at the time of reporting, with an age range of 2 to 34 years. Blood and (or) cerebrospinal fluid lactate were elevated in all 8 patients. MRI in 7 cases manifested symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia. Urine organic acid test were all normal but 1 patient had alanine elevation. Five patients underwent respiratory chain enzyme activity testing, and all had varying degrees of enzyme activity reduction. Six variants were identified, 6 patients were homozygous variants, with c.322-10G>A was present in 4 patients from 2 families and 2 compound heterozygous variants. Conclusions: The clinical phenotype of COXPD32 is highly heterogenous and the severity of the disease varies from development delay, feeding difficulty, dystonia, high lactic acid, ocular symptoms and reduced mitochondrial respiratory chain enzyme activity in mild cases, which may survive into adulthood, to rapid death due to respiratory and circulatory failure in severe cases. COXPD32 needs to be considered in cases of unexplained acidosis, hyperlactatemia, feeding difficulties, development delay or regression, ocular symptoms, respiratory and circulatory failure, and symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia, and genetic testing can clarify the diagnosis.
Humans ; Male ; Acidosis, Lactic ; Brain ; Brain Stem ; Dystonia ; Dystonic Disorders ; Mitochondrial Diseases ; Infant

OBJECTIVE: To analyze the clinical phenotype and genetic variants of a child suspected for mitochondrial F-S disease. METHODS: A child with mitochondrial F-S disease who visited Department of Neurology, Hunan Provincial children's Hospital on November 5, 2020 was selected as research subject of this study. Clinical data of the child was collected. The child was subjected to whole exome sequencing (WES). Bioinformatics tools were used to analyze the pathogenic variants. Candidate variants were verified by Sanger sequencing of the child and her parents. RESULTS: WES revealed that the child has harbored compound heterozygous variants of the FDXR gene, namely c.310C>T (p.R104C) and c.235C>T (p.R79C), which were inherited from her father and mother, respectively. Neither variant has been reported in HGMD, PubMed, 1000 Genomes, and dbSNP databases. Both of the variants have been suggested as deleterious according to the prediction results from different bioinformatics analysis software. CONCLUSION Mitochondrial diseases should be suspected for patients with multiple system involvement. The compound heterozygous variants of the FDXR gene probably underlay the disease in this child. Above finding has enriched the spectrum of FDXR gene mutations underlying mitochondrial F-S disease. WES can facilitate the diagnosis of mitochondrial F-S disease at the molecular level.
Female ; Humans ; Exome Sequencing ; Mitochondrial Diseases/genetics* ; Mothers ; Mutation ; Phenotype ; Child

Objective To study the effect and mechanism of blueberry on regulating the mitochondrial inner membrane protein mitofilin/Mic60 in an in vitro model of metabolic dysfunction-associated liver disease (MAFLD). Methods L02 human hepatocytes were induced by free fatty acids (FFA) to establish MAFLD cell model. A normal group, a model group, an 80 μg/mL blueberry treatment group, a Mic60 short hairpin RNA (Mic60 shRNA) transfection group, and Mic60 knockdown combined with an 80 μg/mL blueberry treatment group were established. The intracellular lipid deposition was observed by oil red O staining, and the effect of different concentrations of blueberry pulp on the survival rate of L02 cells treated with FFA was measured by MTT assay. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) contents were measured by visible spectrophotometry. The expression of reactive oxygen species (ROS) in hepatocytes was observed by fluorescence microscopy, and the mRNA and protein expression of Mic60 were detected by real-time quantitative PCR and Western blot analysis, respectively. Results After 24 hours of FFA stimulation, a large number of red lipid droplets in the cytoplasm of L02 cells was observed, and the survival rate of L02 cells treated with 80 μg/mL blueberry was higher. The results of ALT, AST, TG, TC, MDA and the fluorescence intensity of ROS in blueberry treated group were lower than those in model group, while the levels of SOD, GSH, Mic60 mRNA and protein in blueberry treated group were higher than those in model group. Conclusion Blueberry promotes the expression of Mic60, increases the levels of SOD and GSH in hepatocytes, and reduces the production of ROS, thus alleviating the injury of MAFLD hepatocytes and regulating the disorder of lipid metabolism.
Humans ; Blueberry Plants/chemistry* ; Hepatocytes/metabolism* ; Liver/metabolism* ; Liver Diseases/metabolism* ; Reactive Oxygen Species/metabolism* ; Superoxide Dismutase/metabolism* ; Superoxides/metabolism* ; Mitochondrial Membranes/metabolism* ; Mitochondrial Proteins/metabolism* ; Plant Extracts/pharmacology*

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are the physical connection sites between mitochondria and endoplasmic reticulum (ER). As the compartments controlling substance and information communications between ER and mitochondria, MAMs were involved in the regulation of various pathophysiological processes, such as calcium homeostasis, mitochondrial morphology and function, lipid metabolism and autophagy. In the past decades, accumulating lines of evidence have revealed the pivotal role of MAMs in diverse cardiovascular diseases (CVD). Aging is one of the major independent risk factors for CVD, which causes progressive degeneration of the cardiovascular system, leading to increased morbidity and mortality of CVD. This review aims to summarize the research progress of MAMs in age-related CVD, and explore new targets for its prevention and treatment.
Humans ; Mitochondrial Membranes ; Cardiovascular Diseases/metabolism* ; Calcium Signaling/physiology* ; Mitochondria/physiology* ; Endoplasmic Reticulum/metabolism*

To evaluate e-cigarette vaping-induced respiratory toxicity and the interventional effects of air cleaners. A randomized controlled trial study of toxic vaping by the respiratory tract were conducted at the Key Laboratory of Environmental Medical Engineering, Ministry of Education, the School of Public Health, Southeast University from January to December 2022. 8-week-old male C57BL/6JGpt mice selected with a random number table method were used to establish a vaping-exposure model at different periods (0 d, 3 d, 7 d or 14 d), or exposed to clean air as a control group. Mice were exposed to regular heated vaping (200 ℃) and high-temperature heated vaping (280 ℃). Total lung RNA was extracted from control and e-cigarette exposed mice for transcriptome sequencing analysis. Reactive Oxygen Species (ROS) generation and mitochondrial membrane potential (MMP) were detected by flow cytometry. Total superoxide dismutase (SOD) and superoxide (O^2-) were evaluated using a microplate reader. Real-Time Quantitative PCR (RT-qPCR) was used to detect gene expression. Air filter and ionizer were used to intervene the toxicity of vaping. Data were expressed as (x¯±s), differences between multiple groups were compared using one-way or two-way ANOVA. The results showed that, RNA sequencing assays suggested that the differential genes between the control and vaping exposure groups were significantly enriched in the oxidative stress (Fold Enrichment=3.18) and mitochondrial oxidative phosphorylation (OXPHOS) (Fold Enrichment=5.74) pathways. Both types of heated vaping exposure caused significantly increased the score of alveolitis (F=10.8, P<0.001), increased endogenous ROS generation (F=16.8, P<0.001), decreased MMP (F=13.6, P<0.01), and gene expression of mitochondrial complex I dysfunction. The toxic effects of high-temperature heated vaping were stronger compared to regular heated vaping (F=2.9, P<0.05). The filter demonstrated better protective effects against vaping than the ionizer by reducing pulmonary alveolitis (F=7.4, P<0.01). Air cleaners could partially alleviate oxidative stress and mitochondrial dysfunction. In conclusion, this study demonstrate that vaping brings potential health risks. Air cleaners could partially reverse mitochondrial dysfunction, but cannot completely prevent the toxic effects, effective interventions remain to be investigated.
Humans ; Male ; Animals ; Mice ; Mice, Inbred C57BL ; Electronic Nicotine Delivery Systems ; Reactive Oxygen Species ; Vaping ; Mitochondrial Diseases

Objective: To explore the clinical features of hepatocerebral mitochondrial DNA depletion syndrome (MDS). Methods: The clinical data of 6 hepatocerebral MDS patients diagnosed in the Jinshan Hospital of Fudan University from January 2012 to December 2019 were retrospectively collected and analyzed. Related literature published before January 2020 were searched with the key words of "DGUOK""MPV17""POLG""C10orf2" in PubMed, China national knowledge infrastructure (CNKI) and Wanfang database. Results: All the 6 hepatocerebral MDS cases were male. The age of onset ranged from 3 days to 8 months. The most common initial symptoms were cholestasis and developmental retrogression. The main clinical manifestations included hepatomegaly (4 cases), hypotonia (3 cases), growth retardation (4 cases), cholestasis (5 cases), coagulopathy (5 cases), hypoalbuminemia (3 cases), hypoglycemia (4 cases), hyperlactacidemia (5 cases), and abnormal blood metabolism screening (6 cases). The isotope hepatobiliary imaging revealed no gallbladder and intestinal tract development within 24 hours in 2 patients. Regarding the cranial imaging examination, the head CT found widening of the extracranial space in 1 case, the brain magnetic resonance imaging (MRI) found ventricular enlargement in 2 cases, and the brain ultrasound found peripheral white matter injury in 1 case. Two cases were lost to follow-up, one died of liver failure, and three died of multiple organ failure due to aggravated infection. Among the 6 cases, there were 3 with MPV17 variation (c.182T>C and c.279G>C were novel), 1 with POLG variation (c.2993G>A was novel), 1 with DGUOK variation (c.679G>A homozygous mutation, parthenogenetic diploid of chromosome 2) and 1 with C10orf2 variation (c.1186C>T and c.1504C>T were novel). The literature review found that 129, 100, 51 and 12 cases of hepatocerebral MDS were caused by DGUOK, MPV17, POLG and C10orf2 gene variations, respectively. And the most common clinical manifestations were liver dysfunction presented with cholestasis and elevated transaminase, metabolic disorders including hypoglycemia and hyperlactacidemia, and diverse neurologic symptoms including developmental retardation, hypotonia, epilepsy and peripheral neuropathy. Besides, 1/3 of the patients with C10orf2 variation developed renal tubular injury. Conclusions: Hepatocerebral MDS mainly present with liver dysfunction, metabolic disorder and neuromuscular impairment. Different genotypes show specific clinical manifestations.
Cholestasis ; DNA, Mitochondrial/genetics* ; Female ; Humans ; Hypoglycemia/genetics* ; Infant ; Liver Diseases/genetics* ; Male ; Mitochondrial Diseases ; Muscle Hypotonia ; Retrospective Studies