Oxidative Stress Mitochondrial Dysfunction Research Articles

A Comprehensive Review of the Contribution of Mitochondrial DNA Mutations and Dysfunction in Polycystic Ovary Syndrome, Supported by Secondary Database Analysis

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting women of reproductive age characterized by a spectrum of clinical, metabolic, reproductive, and psychological abnormalities. This syndrome is associated with significant long-term health risks, necessitating elucidation of its pathophysiology, early diagnosis, and comprehensive management strategies. Several contributory factors in PCOS, including androgen excess and insulin resistance, collectively enhance oxidative stress, which subsequently leads to mitochondrial dysfunction. However, the precise mechanisms through which oxidative stress induces mitochondrial dysfunction remain incompletely understood. Comprehensive searches of electronic databases were conducted to identify relevant studies published up to 30 September 2024. Mitochondria, the primary sites of reactive oxygen species (ROS) generation, play critical roles in energy metabolism and cellular homeostasis. Oxidative stress can inflict damage on components, including lipids, proteins, and DNA. Damage to mitochondrial DNA (mtDNA), which lacks efficient repair mechanisms, may result in mutations that impair mitochondrial function. Dysfunctional mitochondrial activity further amplifies ROS production, thereby perpetuating oxidative stress. These disruptions are implicated in the complications associated with the syndrome. Advances in genetic analysis technologies, including next-generation sequencing, have identified point mutations and deletions in mtDNA, drawing significant attention to their association with oxidative stress. Emerging data from mtDNA mutation analyses challenge conventional paradigms and provide new insights into the role of oxidative stress in mitochondrial dysfunction. We are rethinking the pathogenesis of PCOS based on these database analyses. In conclusion, this review explores the intricate relationship between oxidative stress, mtDNA mutations, and mitochondrial dysfunction, offers an updated perspective on the pathophysiology of PCOS, and outlines directions for future research.

Bladder cancer associated with elevated heavy metals: Investigation of probable carcinogenic pathways through mitochondrial dysfunction, oxidative stress and mitogen-activated protein kinase

ObjectiveCarcinogenic mechanisms of heavy metals/ trace elements (HMTE) in bladder cancer (BC) are exactly unknown. Mitochondrial dysfunction (MD), oxidative stress (OS), and mitogen-activated protein kinases (MAPK) are probable carcinogenic mechanisms. The purpose is to investigate probable carcinogenic pathways of HMTE in BC using six MD genes, seven OS markers, and p38-MAPK. MethodsStudy included 125 BC/radical cystectomy (RC) patients between October 2020 and October 2022, and 72 controls. Exclusion criteria included previous neoplasm, chemo- or radiotherapy. Two samples (cancer/noncancer) were taken from RC specimens. Tissues/plasma/urine cadmium (Cd), lead (Pb), cobalt (Co), nickel (Ni), strontium (Sr), aluminium (Al), zinc (Zn), boron (B) were measured by ICP-OES. Tissue MD genes (mt-CO3, mt-CYB, mt-ATP 6, mt-ATP8, mt-CO1, mt-ND1), and serum OS markers (8-OHdG, MDA, 3-NT, AGEs, AOPP, ROS, SOD2), p38-MAPK were assessed by RT-PCR, and ELISA, respectively. ResultsBC and adjacent tissue showed higher (Al, Co, Pb, Ni, Zn, Cd,Sr), lower B concentrations, compared to controls. High tissue concentrations (Cd, Co, Pb, Ni, Sr) were associated with higher MD genes, OS, MAPK and lower SOD2 levels. The same differences were greater in 41 patients with concomitant elevation of two or more HMTE. Noninclusion of BC-related oncogenes (e.g. RAS) is a limitation. ConclusionsEvidence suggests that high BC tissue (Cd, Co, Pb, Ni, Si) concentrations are associated with over-expressed MD genes, OS, p38-MAPK and low SOD2. These findings provide important understanding keys of probable carcinogenic pathways in BC associated with HMTE. So, efforts should be performed to minimize and counteract exposure to toxic HMTE.

Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer's Disease.

Although the basis of Alzheimer’s disease (AD) etiology remains unknown, oxidative stress (OS) has been recognized as a prodromal factor associated to its progression. OS refers to an imbalance between oxidant and antioxidant systems, which usually consist in an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which overwhelms the intrinsic antioxidant defenses. Due to this increased production of ROS and RNS, several biological functions such as glucose metabolism or synaptic activity are impaired. In AD, growing evidence links the ROS-mediated damages with molecular targets including mitochondrial dynamics and function, protein quality control system, and autophagic pathways, affecting the proteostasis balance. In this scenario, OS should be considered as not only a major feature in the pathophysiology of AD but also a potential target to combat the progression of the disease. In this review, we will discuss the role of OS in mitochondrial dysfunction, protein quality control systems, and autophagy associated to AD and suggest innovative therapeutic strategies based on a better understanding of the role of OS and proteostasis.

Neuroprotective effects of brimonidine on retinal ganglion cells induced by oxidative stress mitochondrial dysfunction

Objective To explore whether brimonidine has a protective effect on retinal ganglion cells (RGCs) through improving mitochondrial function under the oxidative stress. Methods Mouse RGC-5 cells were cultured in DMEM medium containing low concentration of glucose (1 g/L), 10% fetal bovine serum and 100 U/ml penicillin-streptomycin solution.The cells were divided into normal control group, H2O2-treated group and brimonidine+ H2O2 group.H2O2 at the concentration of 800 μmol/L was added into the medium in the H2O2-treated group, and 1 μmol/L brimonidine was added into the medium for 2 hours prior to the addition of H2O2 in the brimonidine+ H2O2 group.The cells were sequently cultured for 24 hours.The morphology of the cell nucleus was examined by Hoechst fluorscence staining.The expressions of apoptosis-related protein in the cells were detected by Western blot assay.Mitochondrial membrane potential was assessed by JC-1 staining. Results The cell nuclei showed round or oval in shape with consistent size in the normal control group.The pycnosis and karyorrhexis of the cell nuclei were seen in the H2O2-treated group, and less abnormal nuclei were found in the brimonidine+ H2O2 group.The relative expression level of bcl-2 protein in the cells was 0.76±0.15, 0.50±0.13 and 0.75±0.17 in the normal control group, H2O2-treated group and brimonidine+ H2O2 group, respectively, and the expression of bcl-2 protein in the H2O2-treated group was significantly lower than that in the normal control group and brimonidine+ H2O2 group (both at P<0.05). The relative expression level of bax protein in the cells was 0.65±0.13, 0.83±0.07 and 0.70±0.10 in the normal control group, H2O2-treated group and brimonidine+ H2O2 group, respectively, and the expression of bax protein in the H2O2-treated group was significantly higher than that in the normal control group and brimonidine+ H2O2 group (both at P<0.05). A strong orange fluorescence was seen in the mitochondrial membrane of RGC-5 in the normal control group with a co-expression with the green fluorescence of cell membrane.In the H2O2-treated group, the orange fluorescence intensity in the cells was evidently weakened, and the number of JC-1 responsed cells was considerably increased and the orange fluorescence intensity was enhanced in the brimonidine+ H2O2 group. Conclusions Brimonidine can prevent RGCs from oxidative-stress damage by improving the mitochondrial function and therefore play a potential neuroprotective effect on optic nerve. Key words: Neuroprotective agents/pharmacology; Cell hypoxia/drug effects; Oxidative stress; Retinal ganglion cells; Apoptosis; Mitochondria/pathology; Brimonidine; Cell line

Regional Oxidative Stress Disrupts the Normal Propagation of Voltage Waves and Promotes Reentry in Monolayers of Cardiac Myocytes

It has been suggested that the oxidative stress due to ischemic injury plays an important role in arrhythmogenesis. Reactive oxygen species can activate the mitochondrial inner membrane anion channel causing mitochondrial depolarization, which can lead to arrhythmias as we previously showed using experimental and computational models. In particular, our previous experiments showed that coverslip-induced ischemia leads to oxidation of GSH/GSSG couple. Here, we study the effects of regional depletion of GSH pool on mitochondrial function and propagation of the voltage wave in monolayers of cardiac myocytes. Neonatal rat ventricular myocytes were isolated and cultured on fibronectin-coated plastic coverslips (D = 2.1 cm) for 5-7 days. Mitochondrial inner membrane potential was observed using potentiometric fluorescent dye, TMRM, in the dequench mode (2 μM). Optical mapping was used to record the changes in sarcolemmal membrane potential using voltage-sensitive fluorescent dye, di-4-ANEPPS (5 μM), as the voltage waves elicited by a stimulation pulse train, propagated through the monolayer. A thiol oxidizing agent, diamide (1 mM) was locally perfused in the center part (D = 0.5 cm) of the monolayer, while the rest of the coverslip received normal Tyrode's solution. The resulting GSH oxidation led to mitochondrial depolarization (left figure). Action potential amplitude decrease was followed by complete inexcitability in 20 minutes and reentry occurred in 2 out of 3 monolayers (right figure). There was no incidence of reentry in control. The results emphasize the role of oxidative stress in mitochondrial dysfunction and the following post-ischemic arrhythmias. This work was supported by NIH's R01HL105216 and R37HL54598 (B.O'R.) and AHA's 14POST20000018 (S.S.).