Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease

Mangrulkar, Shubhada V.; Wankhede, Nitu L.; Kale, Mayur B.; Upaganlawar, Aman; Taksande, Brijesh G.; Umekar, Milind J.; Anwer, Md. Khalid; Dailah, Hamad Ghaleb; Mohan, Syam; Behl, Tapan

doi:10.1007/s12640-023-00647-2

Cited by 12 publications

(8 citation statements)

References 233 publications

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“…Mitochondria are highly active organelles responsible for ATP generation as well as basic cellular activities, such as cell survival and death, redox state, and responding to external stimuli. Disturbances in the balance of mitochondrial dynamics, as evidenced by a shift toward fission, have been linked to a range of illnesses, including AD [37]. A growing body of evidence indicates that microglial activation and neuroinflammation are linked to Following that, changes in the mitochondrial membrane potential (MMP) of microglia cells were examined after the cells were stained with JC-10, a cationic dye that is able to selectively accumulate in mitochondria and which reversibly changes color from green to red as membrane potential increases.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Modified TPP-MoS2 QD Blend as a Bio-Functional Model for Normalizing Microglial Dysfunction in Alzheimer’s Disease

Alomari

Qusti

Balgoon

et al. 2023

Neurology International

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Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease of old age. Accumulation of β-amyloid peptide (Aβ) and mitochondrial dysfunction results in chronic microglial activation, which enhances neuroinflammation and promotes neurodegeneration. Microglia are resident macrophages of the brain and spinal cord which play an important role in maintaining brain homeostasis through a variety of phenotypes, including the pro-inflammatory phenotype and anti-inflammatory phenotypes. However, persistently activated microglial cells generate reactive species and neurotoxic mediators. Therefore, inhibitors of microglial activation are seen to have promise in AD control. The modified TPP/MoS2 QD blend is a mitochondrion-targeted nanomaterial that exhibits cytoprotective activities and antioxidant properties through scavenging free radicals. In the present study, the cell viability and cytotoxicity of the DSPE-PEG-TPP/MoS2 QD blend on microglial cells stimulated by Aβ were investigated. The levels of reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were also assessed. In addition, pro-inflammatory and anti-inflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), transforming growth factor beta (TGF-β), inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-I) were measured in the presence or absence of the DSPE-PEG-TPP/MoS2 QD blend on an immortalized microglia cells activated by accumulation of Aβ. We found that the DSPE-PEG-TPP/MoS2 QD blend was biocompatible and nontoxic at specific concentrations. Furthermore, the modified TPP/MoS2 QD blend significantly reduced the release of free radicals and improved the mitochondrial function through the upregulation of MMP in a dose-dependent manner on microglial cells treated with Aβ. In addition, pre-treatment of microglia with the DSPE-PEG-TPP/MoS2 QD blend at concentrations of 25 and 50 μg/mL prior to Aβ stimulation significantly inhibited the release and expression of pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and iNOS. Nevertheless, the anti-inflammatory cytokines TGF-β and Arg-I were activated. These findings suggest that the modified TPP/MoS2 QD blend reduced oxidative stress, inflammation and improved the mitochondrial function in the immortalized microglial cells (IMG) activated by Aβ. Overall, our research shows that the DSPE-PEG-TPP/MoS2 QD blend has therapeutic promise for managing AD and can impact microglia polarization.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Modified TPP-MoS2 QD Blend as a Bio-Functional Model for Normalizing Microglial Dysfunction in Alzheimer’s Disease

Alomari

Qusti

Balgoon

et al. 2023

Neurology International

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“…137 Furthermore, a large amount of evidence indicating that mtDNA mutations can impair the normal function of mitochondria, leading to mitochondrial dysfunction that, in turn, can disrupt mitophagy, has been reviewed. 138, 139 Mitochondrial DNA mutations can be responsible for defects in mitochondrial respiratory chain complexes, leading to reduced ATP production, increased production of ROS, and altered mitochondrial membrane potential. A study using cybrid cell lines with some point mutations in mtDNA suggested that aging-related mtDNA mutations can lead to mitochondrial dysfunction by altering the oxidative phosphorylation mechanism.…”

Section: Defective Mitophagy and Mtdna Mutationsmentioning

confidence: 99%

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

Orekhov,

Summerhill,

Khotina

et al. 2023

Gene Expr

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Inflammation is a natural reaction of the innate immune system that evolved primarily to protect the human body from invading pathogens and to heal injuries. There are two different types of inflammation, acute and chronic inflammation, differing in duration, underlying causes, and characteristics. The acute-to-chronic transition can be determined by several pathomechanisms, including dysregulation of immune response and failure to eliminate the underlying cause. Moreover, epigenetic changes that refer to modifications in gene expression that are heritable but do not involve changes to the underlying DNA sequence can also contribute to prolonged inflammation. Emerging evidence suggests that dysfunctional mitochondria can promote the development of chronic inflammation. In this respect, the mechanisms triggering defective mitophagy, a selective form of autophagy that exterminates dysfunctional mitochondria to maintain cellular homeostasis, attracted special attention. The hypothesis on the pivotal role of mutations in mitochondrial DNA causing defective mitophagy stimulated the area of the research that applies editing of the mitochondrial genome. The mitoCAS9 vector and two single guide RNAs to the G15059A mutation were used to eliminate the mutation from the macrophage-like cells. The normal activity of the initially defective mitophagy was restored in intact macrophage-like cells, confirming the causal role of the G15059A mutation in the disruption of the mitophagy process. The unraveling of the underlying mechanisms of chronic inflammation will help to develop targeted therapeutic approaches aimed at restoring mitochondrial health and alleviating chronic inflammation that can be used for the treatment of a wide range of chronic inflammatory diseases.

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“…The mitochondrial hypothesis of aging suggests that mitochondrial dysfunction over time leads to a decrease in cellular energy production, increased oxidative stress, calcium dysregulation, accumulation of mutations in mitochondrial DNA (mtDNA), apoptosis, alterations in mitochondrial dynamics (fusion and fission), accumulation of cellular waste products, disturbed mitophagy, and changes in cellular metabolism [ 27 , 28 , 29 , 30 ]. This, in turn, may be the biological basis for the development of age-related diseases, including neurodegenerative diseases, and the possibility of their treatment [ 31 , 32 , 33 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Mitochondrial dysfunctions are implicated in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease, and Huntington’s disease [ 6 , 31 , 35 ]. Common features in their pathogenesis are mitochondrial dysfunction, progressive neurodegeneration, and cognitive decline leading to dementia.…”

Section: Introductionmentioning

confidence: 99%

Age-Dependent Alterations in Platelet Mitochondrial Respiration

et al. 2023

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Mitochondrial dysfunction is an important cellular hallmark of aging and neurodegeneration. Platelets are a useful model to study the systemic manifestations of mitochondrial dysfunction. To evaluate the age dependence of mitochondrial parameters, citrate synthase activity, respiratory chain complex activity, and oxygen consumption kinetics were assessed. The effect of cognitive impairment was examined by comparing the age dependence of mitochondrial parameters in healthy individuals and those with neuropsychiatric disease. The study found a significant negative slope of age-dependence for both the activity of individual mitochondrial enzymes (citrate synthase and complex II) and parameters of mitochondrial respiration in intact platelets (routine respiration, maximum capacity of electron transport system, and respiratory rate after complex I inhibition). However, there was no significant difference in the age-related changes of mitochondrial parameters between individuals with and without cognitive impairment. These findings highlight the potential of measuring mitochondrial respiration in intact platelets as a means to assess age-related mitochondrial dysfunction. The results indicate that drugs and interventions targeting mitochondrial respiration may have the potential to slow down or eliminate certain aging and neurodegenerative processes. Mitochondrial respiration in platelets holds promise as a biomarker of aging, irrespective of the degree of cognitive impairment.

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Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease

Cited by 12 publications

References 233 publications

Modified TPP-MoS2 QD Blend as a Bio-Functional Model for Normalizing Microglial Dysfunction in Alzheimer’s Disease

Modified TPP-MoS2 QD Blend as a Bio-Functional Model for Normalizing Microglial Dysfunction in Alzheimer’s Disease

Role of Mitochondria in the Chronification of Inflammation: Focus on Dysfunctional Mitophagy and Mitochondrial DNA Mutations

Age-Dependent Alterations in Platelet Mitochondrial Respiration

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