scholarly journals Mitochondrial Function and Parkinson’s Disease: From the Perspective of the Electron Transport Chain

2021 ◽  
Vol 14 ◽  
Author(s):  
Jeng-Lin Li ◽  
Tai-Yi Lin ◽  
Po-Lin Chen ◽  
Ting-Ni Guo ◽  
Shu-Yi Huang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Direct Evidence ◽  
Complex Iii ◽  
Complex Iv ◽  
Transport Chain ◽  
Mitochondrial Functions

Parkinson’s disease (PD) is known as a mitochondrial disease. Some even regarded it specifically as a disorder of the complex I of the electron transport chain (ETC). The ETC is fundamental for mitochondrial energy production which is essential for neuronal health. In the past two decades, more than 20 PD-associated genes have been identified. Some are directly involved in mitochondrial functions, such as PRKN, PINK1, and DJ-1. While other PD-associate genes, such as LRRK2, SNCA, and GBA1, regulate lysosomal functions, lipid metabolism, or protein aggregation, some have been shown to indirectly affect the electron transport chain. The recent identification of CHCHD2 and UQCRC1 that are critical for functions of complex IV and complex III, respectively, provide direct evidence that PD is more than just a complex I disorder. Like UQCRC1 in preventing cytochrome c from release, functions of ETC proteins beyond oxidative phosphorylation might also contribute to the pathogenesis of PD.

Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria

2008 ◽  
Vol 294 (2) ◽  
pp. C460-C466 ◽  
Author(s):  
Qun Chen ◽  
Shadi Moghaddas ◽  
Charles L. Hoppel ◽  
Edward J. Lesnefsky
Keyword(s):  
Electron Transport ◽  
Complex I ◽  
Electron Transport Chain ◽  
Myocardial Injury ◽  
Complex Iii ◽  
Ischemic Damage ◽  
Ros Production ◽  
Oxygen Species ◽  
Net Production ◽  
Transport Chain

Cardiac ischemia decreases complex III activity, cytochrome c content, and respiration through cytochrome oxidase in subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM). The reversible blockade of electron transport with amobarbital during ischemia protects mitochondrial respiration and decreases myocardial injury during reperfusion. These findings support that mitochondrial damage occurs during ischemia and contributes to myocardial injury during reperfusion. The current study addressed whether ischemic damage to the electron transport chain (ETC) increased the net production of reactive oxygen species (ROS) from mitochondria. SSM and IFM were isolated from 6-mo-old Fisher 344 rat hearts following 25 min global ischemia or following 40 min of perfusion alone as controls. H2O2release from SSM and IFM was measured using the amplex red assay. With glutamate as a complex I substrate, the net production of H2O2was increased by 178 ± 14% and 179 ± 17% in SSM and IFM ( n = 9), respectively, following ischemia compared with controls ( n = 8). With succinate as substrate in the presence of rotenone, H2O2increased by 272 ± 22% and 171 ± 21% in SSM and IFM, respectively, after ischemia. Inhibitors of electron transport were used to assess maximal ROS production. Inhibition of complex I with rotenone increased H2O2production by 179 ± 24% and 155 ± 14% in SSM and IFM, respectively, following ischemia. Ischemia also increased the antimycin A-stimulated production of H2O2from complex III. Thus ischemic damage to the ETC increased both the capacity and the net production of H2O2from complex I and complex III and sets the stage for an increase in ROS production during reperfusion as a mechanism of cardiac injury.

Environmental toxins and Parkinson’s disease: Putative roles of impaired electron transport chain and oxidative stress

2010 ◽  
Vol 26 (2) ◽  
pp. 121-128 ◽  
Author(s):  
Ibrahim Abdulwahid Arif ◽  
Haseeb Ahmad Khan
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Electron Transport ◽  
Mitochondrial Respiration ◽  
Electron Transport Chain ◽  
Electron Flow ◽  
Oxidative Modification ◽  
Environmental Toxins ◽  
Transport Chain

Despite recent advancements in the biomedical fields, the etiology and pathogenesis of Parkinson’s disease (PD) is still poorly understood, though the crucial roles of oxidative stress and impaired mitochondrial respiration have been suggested in the development of PD. The oxidative modification of the proteins of mitochondrial electron transport chain alters their normal function leading to the state of energy crisis in neurons. Exposure of environmental chemicals such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and rotenone in mouse produces the symptoms akin to PD and therefore these neurotoxins are commonly used in experimental studies on PD. Another environmental toxin, paraquat (a commonly used herbicide) has also been implicated with the onset of PD. The neurotoxicity of these chemicals is accompanied by the blockade of electron flow from NADH dehydrogenase to coenzyme Q. The agents with the ability to improve mitochondrial respiration and ATP production have been shown to exert beneficial effects in PD patients as well as in the animal models of PD. This review summarizes the current research implicating the impairment of mitochondrial respiratory chain and the role of environmental toxins in the pathogenesis of PD.

scholarly journals Targeting the complex I and III of mitochondrial electron transport chain as a potentially viable option in liver cancer management

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qin Yang ◽  
Ling Wang ◽  
Jiaye Liu ◽  
Wanlu Cao ◽  
Qiuwei Pan ◽  
...  
Keyword(s):  
Electron Transport ◽  
Liver Cancer ◽  
Therapeutic Target ◽  
Complex I ◽  
Electron Transport Chain ◽  
Metabolic Reprogramming ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Potential Therapeutic Target ◽  
Transport Chain

AbstractLiver cancer is one of the most common and lethal types of oncological disease in the world, with limited treatment options. New treatment modalities are desperately needed, but their development is hampered by a lack of insight into the underlying molecular mechanisms of disease. It is clear that metabolic reprogramming in mitochondrial function is intimately linked to the liver cancer process, prompting the possibility to explore mitochondrial biochemistry as a potential therapeutic target. Here we report that depletion of mitochondrial DNA, pharmacologic inhibition of mitochondrial electron transport chain (mETC) complex I/complex III, or genetic of mETC complex I restricts cancer cell growth and clonogenicity in various preclinical models of liver cancer, including cell lines, mouse liver organoids, and murine xenografts. The restriction is linked to the production of reactive oxygen species, apoptosis induction and reduced ATP generation. As a result, our findings suggest that the mETC compartment of mitochondria could be a potential therapeutic target in liver cancer.

scholarly journals Steady-state kinetic analysis of mitochondrial respiratory enzymes from bovine heart mitochondria

2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Dayoung Kim ◽  
Eun Ko ◽  
Moonsung Choi ◽  
Sooim Shin
Keyword(s):  
Steady State ◽  
Electron Transport ◽  
Kinetic Analysis ◽  
Kinetic Parameters ◽  
Complex I ◽  
Electron Transport Chain ◽  
Complex Iii ◽  
Steady State Kinetic ◽  
Transport Chain ◽  
State Kinetic

AbstractMitochondria is a decisive organelle of cells that produces adenosine triphosphate (ATP) by the process of oxidative phosphorylation of the Krebs cycle and the electron transport chain. The electron transport chain system of mitochondria embodies multiple enzyme supercomplexes including complex I to V which located in the inner membrane. Although the simple enzyme activity of some as-isolated complex has been studied so far, the steady-state kinetic analysis of each complex within the form of mitochondrial supercomplex has not been studied in depth. To this end, kinetic parameters of mitochondrial complex I–IV were determined using steady-kinetic analysis using corresponding substrates of them. Catalytic activity and binding affinity between substrates and enzymes were obtained by fitting the data to the Michaelis–Menten equation. Acquired kinetic parameters represented distinctive values depending on the complexes that can be interpreted by the characteristics of the enzymes including the distinction of substrates or the ratio of the enzyme itself under the supercomplex form. The indirect kcat of the mitochondrial enzymes were varied from 0.0609 to 0.334 s−1 in order of complex III, II, I, and IV and Km of substrates were also diverse from 5.1 μM to 12.14 mM. This is the first attempt to get exact kinetic values that should provide profound information to evaluate the mitochondrial function practically in advance.

Abstract P302: Alpha-1A Adrenergic Receptor Activation Increases Electron Transport Chain Activity In The Uninjured Mouse Heart

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Peyton B Sandroni ◽  
Matthew R Vander Ploeg ◽  
Wei Huang ◽  
Brian C Jensen
Keyword(s):  
Enzyme Activity ◽  
Electron Transport ◽  
Adrenergic Receptor ◽  
Complex I ◽  
Electron Transport Chain ◽  
Citrate Synthase ◽  
Cardiac Mitochondria ◽  
Complex Iv ◽  
Failing Heart ◽  
Transport Chain

Decreased electron transport chain (ETC) activity in cardiac mitochondria is a hallmark of heart failure. Gain- and loss-of-function studies define the benefits of alpha-1A adrenergic receptor (α1A-AR) activation in the failing heart, such as increased cardiac contractility. However, the mechanisms behind these effects are unknown, and α1A-AR activation as a method of ETC regulation has not been studied. Here, we assessed the hypotheses that decreased α1A-AR activation reduces ETC enzyme activity, whereas increased α1A-AR activation enhances ETC enzyme activity. We profiled citrate synthase and ETC complex I-IV activities in isolated cardiac mitochondria from (1) wild-type (WT) CL57Bl/6J mice or global α1A-AR knockout mice (10-12 wks) and (2) WT mice (10-12 wks) treated with vehicle (0.9% saline) or the selective α1A-AR agonist A61603 (10 ng/kg/d, 3 d). Citrate synthase, a key enzyme in the citric acid cycle, fuels ETC activity and is a commonly used marker for mitochondrial mass. Global α1A-AR knockout increased citrate synthase activity in male mice compared to WT controls (5,292 ± 275 vs. 4,198 ± 339 nmol/min/mg, n = 5 each group, p = 0.04) (mean ± SEM) (Panel A). When normalized to citrate synthase activity, global α1A-AR knockout decreased complex I (37 ± 10% vs. 64 ± 5%, p = 0.02) (1,786 ± 421 vs. 2,766 ± 422 nmol/min/mg) and complex II (25 ± 9% vs. 50 ± 13%, p = 0.01) (1,332 ± 219 vs. 2,032 ± 213 nmol/min/mg) activities with a trend toward decreased complex IV activity (33 ± 13% vs. 49 ± 17%, p = 0.07) (1,707 ± 201 vs. 2,000 ± 238 nmol/min/mg) (Panel B). A61603 treatment led to a trend towards decreased citrate synthase activity in female mice compared to vehicle controls (6,662 ± 501 vs. 7,701 ± 421 nmol/min/mg, n = 3 each group, p = 0.09) (Panel C). When normalized to citrate synthase activity, A61603 increased complex I (27 ± 3% vs. 17 ± 2%, p = 0.03) (1,736 ± 92 vs. 1,326 ± 156 nmol/min/mg), complex III (61 ± 6% vs. 37 ± 5%, p = 0.02) (3,993 ± 258 vs. 2,894 ± 531 nmol/min/mg), and complex IV (70 ± 6% vs. 48 ± 6%, p = 0.03) (4,631 ± 100 vs. 3,676 ± 533 nmol/min/mg) activities (Panel D). In conclusion, we show that global α1A-AR knockout decreases ETC enzyme activity, while treatment with an α1A-AR agonist increases ETC enzyme activity. These findings may identify a novel mechanism through which α1A-AR activation protects the injured and failing heart.

scholarly journals AB0031 T HELPER 17 CELLS WERE SIGNIFICANTLY DECREASED BY MITOCHONDRIAL ELECTRON TRANSPORT CHAIN COMPLEX INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1318.2-1318
Author(s):  
H. R. Lee ◽  
S. J. Yoo ◽  
J. Kim ◽  
I. S. Yoo ◽  
C. K. Park ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Electron Transport ◽  
Disease Activity ◽  
Th17 Cells ◽  
Electron Transport Chain ◽  
Chain Complex ◽  
Complex Iii ◽  
Mitochondrial Electron Transport Chain ◽  
Transport Chain ◽  
Healthy Control

Background:Reactive oxygen species (ROS) and T helper 17 (TH17) cells have been known to play an important role in the pathogenesis of rheumatoid arthritis (RA). However, the interrelationship between ROS and TH17 remains unclear in RAObjectives:To explore whether ROS affect TH17 cells in peripheral blood mononuclear cells (PBMC) of RA patients, we analyzed ROS expressions among T cell subsets following treatment with mitochondrial electron transport chain complex inhibitors.Methods:Blood samples were collected from 40 RA patients and 10 healthy adult volunteers. RA activity was divided according to clinical parameter DAS28. PBMC cells were obtained from the whole blood using lymphocyte separation medium density gradient centrifugation. Following PBMC was stained with Live/Dead stain dye, cells were incubated with antibodies for CD3, CD4, CD8, and CD25. After fixation and permeabilization, samples were stained with antibodies for FoxP3 and IL-17A. MitoSox were used for mitochondrial specific staining.Results:The frequency of TH17 cells was increased by 4.83 folds in moderate disease activity group (5.1>DAS28≥3.2) of RA patients compared to healthy control. Moderate RA activity patients also showed higher ratio of TH17/Treg than healthy control (3.57 folds). All RA patients had elevated expression of mitochondrial specific ROS than healthy control. When PBMC cells were treated with 2.5uM of antimycin A (mitochondrial electron transport chain complex III inhibitor) for 16 h, the frequency of TH17 cells was significantly decreased.Conclusion:The mitochondrial electron transport chain complex III inhibitor markedly downregulated the frequency of TH17 cells in moderate disease activity patients with RA. These findings provide a novel approach to regulate TH17 function in RA through mitochondrial metabolism related ROS production.References:[1]Szekanecz, Z., et al., New insights in synovial angiogenesis. Joint Bone Spine, 2010. 77(1): p. 13-9.[2]Prevoo, M.L., et al., Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum, 1995. 38(1): p. 44-8.Disclosure of Interests:None declared

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