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1.
Mitochondrial Dysfunction and Chronic Inflammation in Polycystic Ovary Syndrome.
Dabravolski, SA, Nikiforov, NG, Eid, AH, Nedosugova, LV, Starodubova, AV, Popkova, TV, Bezsonov, EE, Orekhov, AN
International journal of molecular sciences. 2021;(8)
Abstract
Polycystic ovarian syndrome (PCOS) is the most common endocrine-metabolic disorder affecting a vast population worldwide; it is linked with anovulation, mitochondrial dysfunctions and hormonal disbalance. Mutations in mtDNA have been identified in PCOS patients and likely play an important role in PCOS aetiology and pathogenesis; however, their causative role in PCOS development requires further investigation. As a low-grade chronic inflammation disease, PCOS patients have permanently elevated levels of inflammatory markers (TNF-α, CRP, IL-6, IL-8, IL-18). In this review, we summarise recent data regarding the role of mtDNA mutations and mitochondrial malfunctions in PCOS pathogenesis. Furthermore, we discuss recent papers dedicated to the identification of novel biomarkers for early PCOS diagnosis. Finally, traditional and new mitochondria-targeted treatments are discussed. This review intends to emphasise the key role of oxidative stress and chronic inflammation in PCOS pathogenesis; however, the exact molecular mechanism is mostly unknown and requires further investigation.
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2.
Association of m.5178C>A variant with serum lipid levels: a systematic review and meta-analysis.
Liu, F, He, J, Wang, S, Yu, F, Luo, Z
Bioscience reports. 2021;(12)
Abstract
BACKGROUND Emerging evidence shows that m.5178C>A variant is associated with a lower risk of coronary artery disease (CAD). However, the specific mechanisms remain elusive. Since dyslipidemia is one of the most critical risk factors for CAD and accounts for at least 50% of the population-attributable risk, it is tempting to speculate that the reduced CAD risk caused by the m.5178C>A variant may stem from an improved lipid profile. In order to verify this hypothesis, we conducted the present study to clarify the association of m.5178C>A variant with lipid levels. METHODS By searching ten databases for studies published before 30 June 2021. Thirteen East Asian populations (7587 individuals) were included for the analysis. RESULTS The present study showed that m.5178C>A variant was associated with higher high-density lipoprotein cholesterol (HDL-C) [standardized mean difference (SMD) = 0.12, 95% confidence interval (CI) = 0.06-0.17, P<0.001] and total cholesterol (TC) (SMD = 0.08, 95% CI = 0.02-0.14, P=0.01) levels. In subgroup analysis, the association of m.5178C>A variant with higher HDL-C levels were observed in Japanese (SMD = 0.09, 95% CI = 0.01-0.17, P=0.03) and Chinese populations (SMD = 0.13, 95% CI = 0.07-0.20, P<0.001). However, the association of m.5178C>A variant with lower low-density lipoprotein cholesterol (LDL-C) levels were only observed in Japanese populations (SMD = -0.11, 95% CI = -0.22 to 0.00, P=0.04). CONCLUSIONS The m.5178C>A variant was associated with higher HDL-C and lower LDL-C levels in Japanese populations, which may contribute to decreased CAD risk and longevity of Japanese.
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3.
The role of mitophagy in pulmonary sepsis.
Mohsin, M, Tabassum, G, Ahmad, S, Ali, S, Ali Syed, M
Mitochondrion. 2021;:63-75
Abstract
Sepsis is a systemic inflammatory disease with an unacceptably high mortality rate caused by an infection or trauma that involves both innate and adaptive immune systems. Inflammatory events activate different downstream pathways leading to tissue damage and ultimately multi-organ failure. Mitochondria are responsible for cellular energy, thermoregulation, metabolite biosynthesis, intracellular calcium regulation, and cell death. Damaged mitochondria induce the high Ca2+ influx through mitochondrial calcium uniporter (MCU). It also generates excessive Reactive oxygen species (ROS) and releases mtDNA into the cytoplasm, which causes induction of NLRP3 inflammasome and apoptosis. Mitophagy (Autophagy of damaged mitochondria) controls mitochondrial dynamics and function. It also maintains cellular homeostasis. This review is about how pulmonary sepsis affects the body. What is the aftermath of sepsis, and how mitophagy affects Acute Lung Injury and macrophage polarisation to overcome the damages.
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4.
The Role of Mitochondria in Carcinogenesis.
Kozakiewicz, P, Grzybowska-Szatkowska, L, Ciesielka, M, Rzymowska, J
International journal of molecular sciences. 2021;(10)
Abstract
The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.
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5.
Mitochondrial Function Are Disturbed in the Presence of the Anticancer Drug, 3-Bromopyruvate.
Cal, M, Matyjaszczyk, I, Filik, K, Ogórek, R, Ko, Y, Ułaszewski, S
International journal of molecular sciences. 2021;(12)
Abstract
3-bromopuryvate (3-BP) is a compound with unique antitumor activity. It has a selective action against tumor cells that exhibit the Warburg effect. It has been proven that the action of 3-BP is pleiotropic: it acts on proteins, glycolytic enzymes, reduces the amount of ATP, induces the formation of ROS (reactive oxygen species), and induces nuclear DNA damage. Mitochondria are important organelles for the proper functioning of the cell. The production of cellular energy (ATP), the proper functioning of the respiratory chain, or participation in the production of amino acids are one of the many functions of mitochondria. Here, for the first time, we show on the yeast model that 3-BP acts in the eukaryotic cell also by influence on mitochondria and that agents inhibiting mitochondrial function can potentially be used in cancer therapy with 3-BP. We show that cells with functional mitochondria are more resistant to 3-BP than rho0 cells. Using an MTT assay (a colorimetric assay for assessing cell metabolic activity), we demonstrated that 3-BP decreased mitochondrial activity in yeast in a dose-dependent manner. 3-BP induces mitochondrial-dependent ROS generation which results in ∆sod2, ∆por1, or ∆gpx1 mutant sensitivity to 3-BP. Probably due to ROS mtDNA lesions rise during 3-BP treatment. Our findings may have a significant impact on the therapy with 3-BP.
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6.
Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.
Panchal, K, Tiwari, AK
Mitochondrion. 2021;:118-135
Abstract
Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca2+ homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.
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7.
Mitochondrial DNA A3243G variant-associated retinopathy: a meta-analysis of the clinical course of visual acuity and correlation with systemic manifestations.
Coussa, RG, Sohn, EH, Han, IC, Parikh, S, Traboulsi, EI
Ophthalmic genetics. 2021;(4):420-430
Abstract
PURPOSE The mitochondrial DNA A3243G (m.3243A>G) variant causes a wide spectrum of phenotypes, with pigmentary retinopathy as the most common ocular finding. We undertook this meta-analysis to investigate the clinical course of visual acuity (VA) in patients with m.3243A>G variant and provide key clinical correlations with systemic manifestations. METHODS A PubMed literature search was performed and studies were selected after satisfying pre-set inclusion criteria. Demographic and clinical data, including retinal findings and systemic manifestations were recorded. Cross-sectional and linear regression analyses were used to investigate the relationship between VA and age, as well as between the age at diagnosis of retinopathy and the mean ages at diagnosis of sensorineural hearing loss or diabetes. The age and prevalence of systemic manifestations among patients with and without retinopathy were studied using t-tests and Mann-Whitney U-tests (performed on binarized data). Likelihood ratios were computed. RESULTS The mean VA (average of both eyes) of 90 patients (72.2% female; 65/90) were collected from 18 studies published between 1990 and 2018. The baseline mean age was 45.2 years (range 17 to 92). The mean logMAR VA was 0.10 (- 0.12 to 1.39). There was a statistically significant linear correlation between the logMAR VA and age (p = .008). The VA of patients less than or equal to 50 years of age was significantly better than that of patients older than 50 years (0.06 vs.0.18 logMAR, p = .002). 67 patients (74.4%) showed a characteristic pigmentary retinopathy with a mean age at diagnosis of 47.9 years (17 to 92) and VA of 0.14 logMAR (- 0.12 to 1.24). Age at diagnosis of retinopathy was linearly correlated with age at diagnosis of hearing loss or diabetes (p < .001). Patients with retinopathy were more likely to have hearing loss (83.6% vs. 56.5%, p = .03) or diabetes (56.7% vs. 17.4%, p = .001) than those without retinopathy. Those with both hearing loss and diabetes had an earlier onset of retinopathy than those without (46.4 vs. 60.4 years, p = .01). Patients without both hearing loss and diabetes were 5.3-fold less likely to develop a retinopathy. CONCLUSIONS Patients with m.3243A>G variant pigmentary retinopathy maintain highly functional VA until around the fifth decade of life, after which significant visual decline ensues. Patients without hearing loss and diabetes have a lower likelihood of exhibiting a retinopathy, which tends to appear about one decade after hearing loss and diabetes are diagnosed.
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8.
OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation.
Schöpf, B, Weissensteiner, H, Schäfer, G, Fazzini, F, Charoentong, P, Naschberger, A, Rupp, B, Fendt, L, Bukur, V, Giese, I, et al
Nature communications. 2020;(1):1487
Abstract
Rewiring of energy metabolism and adaptation of mitochondria are considered to impact on prostate cancer development and progression. Here, we report on mitochondrial respiration, DNA mutations and gene expression in paired benign/malignant human prostate tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate and malate in malignant tissue and a significant metabolic shift towards higher succinate oxidation, particularly in high-grade tumors. The load of potentially deleterious mitochondrial-DNA mutations is higher in tumors and associated with unfavorable risk factors. High levels of potentially deleterious mutations in mitochondrial Complex I-encoding genes are associated with a 70% reduction in NADH-pathway capacity and compensation by increased succinate-pathway capacity. Structural analyses of these mutations reveal amino acid alterations leading to potentially deleterious effects on Complex I, supporting a causal relationship. A metagene signature extracted from the transcriptome of tumor samples exhibiting a severe mitochondrial phenotype enables identification of tumors with shorter survival times.
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9.
Mitochondrial Inheritance in Phytopathogenic Fungi-Everything Is Known, or Is It?
Mendoza, H, Perlin, MH, Schirawski, J
International journal of molecular sciences. 2020;(11)
Abstract
Mitochondria are important organelles in eukaryotes that provide energy for cellular processes. Their function is highly conserved and depends on the expression of nuclear encoded genes and genes encoded in the organellar genome. Mitochondrial DNA replication is independent of the replication control of nuclear DNA and as such, mitochondria may behave as selfish elements, so they need to be controlled, maintained and reliably inherited to progeny. Phytopathogenic fungi meet with special environmental challenges within the plant host that might depend on and influence mitochondrial functions and services. We find that this topic is basically unexplored in the literature, so this review largely depends on work published in other systems. In trying to answer elemental questions on mitochondrial functioning, we aim to introduce the aspect of mitochondrial functions and services to the study of plant-microbe-interactions and stimulate phytopathologists to consider research on this important organelle in their future projects.
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10.
Mitochondrial DNA 10158T>C mutation in a patient with mitochondrial encephalomyopathy with lactic acidosis, and stroke-like episodes syndrome: A case-report and literature review (CARE-complaint).
Wang, S, Song, T, Wang, S
Medicine. 2020;(24):e20310
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Abstract
RATIONALE Mitochondrial encephalomyopathy with lactic acidosis and stroke- like episodes (MELAS) syndrome is caused by mitochondrial respiratory chain dysfunction and oxidative phosphorylation disorder. It is a rare clinical metabolic disease involved with multiple systems. PATIENT CONCERNS A 22-year-old patient presented with limb convulsion accompanied by loss of consciousness, headache, partial blindness, blurred vision, and so on. DIAGNOSES Brain magnetic resonance imaging showed a high-intensity area in bilateral occipital cortex, left parietal lobe and cerebellum on diffusion-weighted imaging. These focus did not distribute as vascular territory. The pathological examination of skeletal muscle revealed several succinate dehydrogenase reactive vessels with overreaction and increased content of lipid droplets in some muscle fibers. Genetic testing showed that the patient carried m.10158T>C mutation. INTERVENTIONS She was provided with traditional arginine hydrochloride therapy and orally medication of coenzyme Q (10 mg). OUTCOMES Mitochondrial DNA of blood and hair follicle of patient carried m.10158T>C mutation LESSONS For the suspected patients of MELAS syndrome, if the hot-spot mutation test is negative, more detection sites should be selected.