scholarly journals Hesperetin Nanocrystals Improve Mitochondrial Function in a Cell Model of Early Alzheimer Disease

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1003
Author(s):  
Lukas Babylon ◽  
Rekha Grewal ◽  
Pascal-L. Stahr ◽  
Ralph W. Eckert ◽  
Cornelia M. Keck ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Alzheimer Disease ◽  
Mitochondrial Dysfunction ◽  
Respiratory Chain ◽  
Peroxidase Activity ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Expression Levels ◽  
Atp Levels ◽  
Age Related

Mitochondrial dysfunction represents a hallmark of both brain aging and age-related neurodegenerative disorders including Alzheimer disease (AD). AD-related mitochondrial dysfunction is characterized by an impaired electron transport chain (ETC), subsequent decreased adenosine triphoshpate (ATP) levels, and elevated generation of reactive oxygen species (ROS). The bioactive citrus flavanone hesperetin (Hst) is known to modulate inflammatory response, to function as an antioxidant, and to provide neuroprotective properties. The efficacy in improving mitochondrial dysfunction of Hst nanocrystals (HstN) with increased bioavailability has not yet been investigated. Human SH-SY5Y cells harboring neuronal amyloid precursor protein (APP695) acted as a model for the initial phase of AD. MOCK-transfected cells served as controls. The energetic metabolite ATP was determined using a luciferase-catalyzed bioluminescence assay. The activity of mitochondrial respiration chain complexes was assessed by high-resolution respirometry using a Clarke electrode. Expression levels of mitochondrial respiratory chain complex genes were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The levels of amyloid β-protein (Aβ1-40) were measured using homogeneous time-resolved fluorescence (HTRF). ROS levels, peroxidase activity, and cytochrome c activity were determined using a fluorescence assay. Compared to pure Hst dissolved in ethanol (HstP), SH-SY5Y-APP695 cells incubated with HstN resulted in significantly reduced mitochondrial dysfunction: ATP levels and respiratory chain complex activity significantly increased. Gene expression levels of RCC I, IV, and V were significantly upregulated. In comparison, the effects of HstN on SY5Y-MOCK control cells were relatively small. Pure Hst dissolved in ethanol (HstP) had almost no effect on both cell lines. Neither HstN nor HstP led to significant changes in Aβ1-40 levels. HstN and HstP were both shown to lower peroxidase activity significantly. Furthermore, HstN significantly reduced cytochrome c activity, whereas HstP had a significant effect on reducing ROS in SH-SY5Y-APP695 cells. Thus, it seems that the mechanisms involved may not be linked to altered Aβ production. Nanoflavonoids such as HstN have the potential to prevent mitochondria against dysfunction. Compared to its pure form, HstN showed a greater effect in combatting mitochondrial dysfunction. Further studies should evaluate whether HstN protects against age-related mitochondrial dysfunction and thus may contribute to late-onset AD.

scholarly journals ALS/FTD-associated protein FUS induces mitochondrial dysfunction by preferentially sequestering respiratory chain complex mRNAs

2020 ◽  
Vol 34 (11-12) ◽  
pp. 785-805
Author(s):  
Yueh-Lin Tsai ◽  
Tristan H. Coady ◽  
Lei Lu ◽  
Dinghai Zheng ◽  
Isabel Alland ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Respiratory Chain ◽  
Chain Complex ◽  
Respiratory Chain Complex

Thorium inhibits human respiratory chain complex IV (cytochrome c oxidase)

2021 ◽  
pp. 127546
Author(s):  
Libing Yu ◽  
Zhaozhu Lin ◽  
Xuedan Cheng ◽  
Jian Chu ◽  
Xijian Li ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Respiratory Chain ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Complex Iv

New perspectives on the assembly process of mitochondrial respiratory chain complex cytochrome c oxidase

Mitochondrion ◽  
2002 ◽  
Vol 2 (1-2) ◽  
pp. 117-128 ◽  
Author(s):  
Cristina Ugalde ◽  
Marieke J.H Coenen ◽  
Murtada H Farhoud ◽  
Stefanie Gilinsky ◽  
Werner J.H Koopman ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Cytochrome C Oxidase ◽  
Respiratory Chain ◽  
Chain Complex ◽  
Mitochondrial Respiratory Chain ◽  
Assembly Process ◽  
Respiratory Chain Complex ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mitochondrial Respiratory

MELAS-associated m.5541C>T mutation caused instability of mitochondrial tRNATrp and remarkable mitochondrial dysfunction

2020 ◽  
pp. jmedgenet-2020-107323
Author(s):  
Kunqian Ji ◽  
Yan Lin ◽  
Xuebi Xu ◽  
Wei Wang ◽  
Dongdong Wang ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Respiratory Chain ◽  
Nuclear Dna ◽  
Chain Complex ◽  
Trna Genes ◽  
Full Potential ◽  
Respiratory Chain Complex ◽  
Mitochondrial Trna ◽  
Taurine Supplementation ◽  
Complex Activities

BackgroundMitochondrial encephalomyopathy with lactic acidosis and stroke-like episode (MELAS) is a group of genetic diseases caused by mutations in mitochondrial DNA and nuclear DNA. The causative mutations of MELAS have drawn much attention, among them, mutations in mitochondrial tRNA genes possessing prominent status. However, the detailed molecular pathogenesis of these tRNA gene mutations remains unclear and there are very few effective therapies available to date.MethodsWe performed muscle histochemistry, genetic analysis, molecular dynamic stimulation and measurement of oxygen consumption rate and respiratory chain complex activities to demonstrate the molecular pathomechanisms of m.5541C>T mutation. Moreover, we use cybrid cells to investigate the potential of taurine to rescue mitochondrial dysfunction caused by this mutation.ResultsWe found a pathogenic m.5541C>T mutation in the tRNATrp gene in a large MELAS family. This mutation first affected the maturation and stability of tRNATrp and impaired mitochondrial respiratory chain complex activities, followed by remarkable mitochondrial dysfunction. Surprisingly, we identified that the supplementation of taurine almost completely restored mitochondrial tRNATrp levels and mitochondrial respiration deficiency at the in vitro cell level.ConclusionThe m.5541C>T mutation disturbed the translation machinery of mitochondrial tRNATrp and taurine supplementation may be a potential treatment for patients with m.5541C>T mutation. Further studies are needed to explore the full potential of taurine supplementation as therapy for patients with this mutation.

scholarly journals Identification of novel genes involved in apoptosis of HIV-infected macrophages using unbiased genome-wide screening

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Simon X. M. Dong ◽  
Frederick S. Vizeacoumar ◽  
Kalpana K. Bhanumathy ◽  
Nezeka Alli ◽  
Cristina Gonzalez-Lopez ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Respiratory Chain ◽  
Cd4 T Cells ◽  
Chain Complex ◽  
Respiratory Chain Complex ◽  
Complex Ii ◽  
Genome Wide ◽  
Latently Infected ◽  
Induced Apoptosis

Abstract Background Macrophages, besides resting latently infected CD4+ T cells, constitute the predominant stable, major non-T cell HIV reservoirs. Therefore, it is essential to eliminate both latently infected CD4+ T cells and tissue macrophages to completely eradicate HIV in patients. Until now, most of the research focus is directed towards eliminating latently infected CD4+ T cells. However, few approaches have been directed at killing of HIV-infected macrophages either in vitro or in vivo. HIV infection dysregulates the expression of many host genes essential for the survival of infected cells. We postulated that exploiting this alteration may yield novel targets for the selective killing of infected macrophages. Methods We applied a pooled shRNA-based genome-wide approach by employing a lentivirus-based library of shRNAs to screen novel gene targets whose inhibition should selectively induce apoptosis in HIV-infected macrophages. Primary human MDMs were infected with HIV-eGFP and HIV-HSA viruses. Infected MDMs were transfected with siRNAs specific for the promising genes followed by analysis of apoptosis by flow cytometry using labelled Annexin-V in HIV-infected, HIV-exposed but uninfected bystander MDMs and uninfected MDMs. The results were analyzed using student’s t-test from at least four independent experiments. Results We validated 28 top hits in two independent HIV infection models. This culminated in the identification of four target genes, Cox7a2, Znf484, Cstf2t, and Cdk2, whose loss-of-function induced apoptosis preferentially in HIV-infected macrophages. Silencing these single genes killed significantly higher number of HIV-HSA-infected MDMs compared to the HIV-HSA-exposed, uninfected bystander macrophages, indicating the specificity in the killing of HIV-infected macrophages. The mechanism governing Cox7a2-mediated apoptosis of HIV-infected macrophages revealed that targeting respiratory chain complex II and IV genes also selectively induced apoptosis of HIV-infected macrophages possibly through enhanced ROS production. Conclusions We have identified above-mentioned novel genes and specifically the respiratory chain complex II and IV genes whose silencing may cause selective elimination of HIV-infected macrophages and eventually the HIV-macrophage reservoirs. The results highlight the potential of the identified genes as targets for eliminating HIV-infected macrophages in physiological environment as part of an HIV cure strategy.

scholarly journals NAD + repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation

2018 ◽  
Vol 32 (11) ◽  
pp. 5913-5926 ◽  
Author(s):  
Janne Purhonen ◽  
Jayasimman Rajendran ◽  
Saara Tegelberg ◽  
Olli-Pekka Smolander ◽  
Eija Pirinen ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Respiratory Chain ◽  
Chain Complex ◽  
Complex Iii ◽  
Respiratory Chain Complex ◽  
Energy Deprivation
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