ObjectiveTo review the advances of the role of mitochondrial dysfunction in the spinal cord injury (SCI) and its relevant treatments. MethodsFocusing on various mechanisms of mitochondrial dysfunction, recent relevant literature at home and abroad was identified to summarize the therapeutic strategies for SCI. ResultsMitochondrial dysfunction is mainly manifested in abnormalities in mitochondrial energy metabolism, mitochondrial oxidative stress, mitochondrial-mediated apoptosis, mitophagy, mitochondrial permeability transition, and mitochondrial biogenesis, playing a vital role in the development of SCI. Drug that enhanced mitochondrial function have been proved beneficial for the treatment of SCI. ConclusionMitochondrial dysfunction can serve as a potential therapeutic target for SCI, providing ideas and basis for the development of SCI therapeutic candidates in the future.
Mitochondrial DNA (mtDNA) is the circulating genome in mitochondria, and it is easy to accumulate oxidative damage, causing mitochondrial dysfunction, and then cell dysfunction, and even tissue and body pathological changes, leading to diseases. As a pro-inflammatory, inflammatory, and even predictive factor, mtDNA is directly involved in the inflammatory response and the pathogenesis of many diseases. This article aims to review the current pathogenesis of mtDNA damage and its pathogenic role in various human diseases.
Objective To investigate the effect of mitochondrial fission mediated by mitochondrial dynamics related protein 1 (DRP1) on glucose metabolism reprogramming in lung cancer cells, and the regulatory mechanism on phosphatidylinositol-3-kinases (PI3K)/protein kinase B (Akt) signaling pathway. Methods Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of DRP1 in lung cancer tissue and lung cancer cells. Mitochondrial fission inhibitor (Mdivi-1) and Mdivi-1+PI3K/Akt signaling pathway activator 740Y-P were used to treat H1299 cells. Mitochondrial fission agonist (WY14643) + signal inhibitor LY294002 were used to intervene PC14 cells. The reagent kit was used to detect the glucose consumption, lactate release, and ATP production of each group of cells. 5-ethynyl-2-deoxyuridine (EdU) labeling experiment was used to detect the proliferation of cells in each group, and acridine orange/ethidium bromide (AO/EB) staining was used to detect the apoptosis of cells in each group. MitoTracker Red CMXRos was used to detect the mitochondrial morphology of each group of cells. Tetramethylrhodamine ethyl ester (TMRE) staining was used to detect the mitochondrial membrane potential of cells. Dihydroethidium (DHE) staining was used to detect the level of reactive oxygen species (ROS) in cells. Western blot was used to detect was used to detect the expression of pyruvate kinase M2 (PKM2), hexokinase 2 (HK2), phosphofructokinase-1 (PFK1), DRP1, phosphorylated DRP1 (p-DRP1), PI3K, Akt, phosphorylated PI3K (p-PI3K), and phosphorylated Ak t(p-Akt) in each group of cells. Results The mRNA expression of DRP1 was significantly increased in lung cancer tissue and lung cancer cells. Mdivi-1 promoted the development of lung cancer and exerts anticancer effects, while activating PI3K/Akt signaling could partially reverse the anticancer effects of Mdivi-1. WY14643 exerted a pro-cancer effect, and inhibiting PI3K/Akt signaling could partially reverse the pro-cancer effect of WY14643, and the differences were statistically significant (all P<0.05). Conclusions In lung cancer, the expression of DRP1 is significantly increased, and DRP1 affects the glycolysis process and proliferation performance of lung cancer cells by regulating the activation of PI3K/Akt signaling.
ObjectiveTo explore the effects and molecular mechanisms of histone methylase G9a inhibitor BIX-01294 on apoptosis in esophageal squamous cell carcinoma (ESCC).MethodsMTT assay and Colony-forming Units were adopted to determine the effects of BIX-01294 on the growth and proliferation of ESCC cell lines EC109 and KYSE150. Flow cytometry was used to analyze the apoptosis status of ESCC cells after the treatment of BIX-01294. The effects of BIX-01294 treatment on the expressions of G9a catalytic product H3K9me2, DNA double-strand break (DSB) markers, and apoptosis-related proteins were detected by Western blotting.ResultsBIX-01294 inhibited the growth of EC109 and KYSE150 cells in a dose-dependent manner (P<0.05), and BIX-01294 with the inhibitory concentration 50% (IC50) significantly inhibited the formation of colony (P<0.05). After 24 hours treatment of BIX-01294 (IC50), the apoptosis rate of EC109 cells increased from 11.5%±2.1% to 42.5%±5.4%, and KYSE150 cells from 7.5%±0.9% to 49.2%±5.2% (P<0.05). The expression level of the G9a catalytic product, H3K9me2, significantly decreased (P<0.05); while the expression of the DSB marker γH2AX was dramatically enhanced (P<0.05). We also found that the mitochondrial apoptosis pathway was activated and the expression levels of cleaved caspase3 and cleaved PARP were significantly elevated (P<0.05).ConclusionBIX-01294, the inhibitor of methyltransferase G9a, prompted apoptosis in ESCC cells by inducing DSB damage and activating mitochondrial apoptosis pathway.
Objective To investigate the changes in mitochondrial morphology, structure and function in rats with severe intermittent hypoxia, as well as the effects of intermittent hypoxia and its severity on cognitive function. Methods A total of 18 rats were selected to construct a model of severe intermittent hypoxia, which were divided into a normal control group, an intermittent air control group, and a 5% intermittent hypoxia group for 8 weeks, with 6 rats in each group. The structural and functional changes of mitochondria in the hippocampal CA1 region were observed. A total of 30 rats were randomly divided into 5 groups: a normal control group, an intermittent air control group, a 5% intermittent hypoxia 4-week group, a 5% intermittent hypoxia 6-week group, and a 5% intermittent hypoxia 8-week group, with 6 rats in each group. The cognitive function of the rats in each group was evaluated by Morris water maze experiment. Results In the mitochondria of the hippocampal CA1 region of severely intermittent hypoxic rats, bilayer membranes or multilayer membranes were visible, the mitochondria were swollen, cristae were broken and vacuolated, and their respiratory function was significantly weakened, the membrane permeability was increased, and the membrane potential was reduced. In the Morris water maze, there was no significant difference in swimming speed between the rats. With the prolongation of intermittent hypoxia action time, the latency of finding the hidden platform in each group of rats increased significantly, and the residence time of the target quadrant decreased significantly. Conclusions Mitochondrial structure in the hippocampal CA1 region of the rat brain is destroyed during severe intermittent hypoxia, and dysfunction and cognitive impairment occur. With the prolongation of intermittent hypoxic injury, the degree of cognitive impairment worsens.
Objective To analyze the clinical characteristics of antimitochondrial antibody (AMA)-associated cardiac injury. Methods AMA positive patients admitted to West China Hospital of Sichuan University between June 2008 and November 2023 were retrospectively selected. They were categorized into the simple cardiac involvement group and the cardiac and skeletal muscle involvement group according to the presence of skeletal muscle injury. Differences in demographic characteristics, serologic indices, cardiac structure and function, and arrhythmias were compared between the two groups. Results A total of 55 AMA-M2 positive patients with myocardial injury were enrolled. There were 18 cases in the simple cardiac involvement group and 37 cases in the cardiac and skeletal muscle involvement group among them. The age (P=0.002) and mortality rate (P=0.031) of the simple cardiac involvement group were higher than those of the cardiac and skeletal muscle involvement group. There were significant differences in biochemical indicators such as lactate dehydrogenase and α-hydroxybutyrate dehydrogenase between the two groups, and the levels of myocardial enzymes such as creatine kinase isoenzyme, myoglobin and troponin T in the cardiac involvement group were lower than those in the cardiac with skeletal muscle involvement group (P<0.05). Meanwhile, there were significant differences in the incidence of atrial premature beats, atrial fibrillation and other arrhythmias between the two groups (P<0.05). In terms of treatment modalities, glucocorticoids and immunosuppressants were used more frequently in the cardiac combined skeletal muscle involvement group than in the cardiac involvement alone group, whereas β-blockers and diuretics were more prevalent in the cardiac involvement alone group (P<0.05). Conclusion Patients with cardiac involvement alone may have a more insidious or rapid progression of the disease, which requires clinicians to pay higher attention to and provide timely and effective treatment, thus improving the overall prognosis and quality of life of the patients.
Leber hereditary optic neuropathy (LHON) is a matrilineal hereditary optic neuropathy in which mitochondrial DNA mutations lead to retinal ganglion cell degeneration. At present, the treatment for LHON is limited. Early symptomatic treatment and medical treatment may improve the vision of patients. In recent years, rapid progress has been made in gene therapy. Many clinical studies have confirmed its safety and efficacy. Monocular gene therapy is helpful to improve the visual function of LHON patients, and it can also improve the visual acuity of uninjected eyes. Patients do not have serious eye or systemic adverse events during the treatment period, showing good safety and tolerance. Studies with larger sample size and longer follow-up time are needed to further verify the efficacy and safety of gene therapy in the future. Gene therapy is expected to become a safe and effective treatment, bringing hope to LHON patients.
Objective To investigate the spectrum of mitochondrial DNA (mtDNA) mutations in Chinese patients with Leber′s hereditary optic neuropathy (LHON). Methods The primary mtDNA mutations (G3460A、G11778A and T14484 C) of 140 patients with LHON were detected by mutation-specific priming polymerase chain reaction (MSP-PCR), heteroduplex-single strand conformation polymorphism polymerase chain reaction (HA-SSCP), restriction fragment length polymorphisms (RFLP) and measurement of DNA sequence. The transmissibility of the patients′ stirps was analyzed.Results In the 140 patients with LHON, G11778A mtDNA primary mutation was found in 130 (92.9%), including 113 males and 17 females; G3460A mutation was found in 2 (1.4%) including 1 male and 1 female; G14484A mutation was found in 8 (5.7% ) including 6 males and 2 females.Conclusion In Chinese patients with LHON, the incidence of G11778A mtDNA mutation is higher than that of G3460A and T14484C. (Chin J Ocul Fundus Dis，2003，19：269-332)
ObjectiveTo investigate the expression of circular RNA mitochondrial fusin 2 (circ-MFN2) in pancreatic cancer and analyze its correlation with clinicopathological features and prognosis.MethodsThe expressions of circ-MFN2 miRNA in 55 cases of pancreatic cancer tissues and serum were detected by qRT-PCR, and analyzed the correlation between circ-MFN2 and clinicopathological factors of pancreatic cancer and prognosis. The sensitivity, specificity and accuracy of expression of circ-MFN2 miRNA in the diagnosis of pancreatic cancer were statistically analyzed. ROC curve was used to analyze its efficacy as a biomarker for early diagnosis of pancreatic cancer.ResultsCompared with paracancerous tissues of pancreatic cancer and serum of healthy control group, circ-MFN2 miRNA was highly expressed in pancreatic cancer tissues and serum, and the difference were all statistically significant (all P<0.05). Chi square test showed that the expression of circ-MFN2 miRNA in pancreatic cancer tissues was not related to age, gender, tumor size, pathological type, and tumor site (P>0.05), but was significantly related to CA19-9 level, TNM stage, tumor differentiation and lymph node metastasis (P<0.05). The sensitivity, specificity and accuracy of expression of circ-MFN2 miRNA for pancreatic cancer were 72.7%, 70.9% and 83.6% respectively, which were all higher than that of CA19-9 (54.5%, 50.9% and 52.7%, P<0.05). Kaplan-Meier analysis showed that the median survival time of pancreatic cancer patients with high expression of circ-MFN2 miRNA was significantly shorter than that of patients with low expression (9.1 months vs 22.3 months, P<0.05). The area under ROC curve of circ-MFN2 miRNA as a serum biomarker for the diagnosis of pancreatic cancer was 0.861 [95%CI (0.775, 1.157), P=0.000]. Cox multivariate analysis showed that the expression of cirC-MFN2 miRNA and lymph node metastasis were independent risk factors for the prognosis of pancreatic cancer patients.ConclusionsCirc-MFN2 miRNA is highly expressed in pancreatic cancer tissues, and it is related to the clinical characteristics and prognosis of patients. It is expected to be a new molecular marker to predict the prognosis of pancreatic cancer.
Objective To investigate the major types and clinical manifestations of mitochondrial DNA (mtDNA)mutations in Chinese patients with Leber′s hereditary optic neuropathy(LHON). Methods A total of 119 patients with bilateral optic neuropathy from 117 pedigrees, including 37 with determinate diagnosis of LHON(group A) and 82 with suspected LHON(group B),were tested for mtDNA mutations by using single-strand conformational polymorphism, mutation-specific primer polymerase chain reaction and sequencing. Pertinent clinical data and history of the patients with the 11778 mutation were collected. Results Nucleotide positions(np)11778 mutation and np 14484 mutation was found in 33 (89.2%) and 3 (8.1%) patients respectively in group A, while np 11778 mutation was obtained in 26（31.7%）in group B. No 3460 mutation was found in group A or B. The clinical manifestations of 59 patients with np 11778 mutation were as follows: acute or chronic visual loss，no ophthalmalgia, the age of onset of 10-25, and either a central or paracentral scotoma in perimetry. The visual recovery rate was 8.6%～11.6%. Conclusion Chinese patients with LHON have a very high incidence of np 11778 mutation and the clinical manifestations of the patients with np 11778 mutation are similar to those of Caucasian patients. (Chin J Ocul Fundus Dis，2004，20：78-80)