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A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions.

Kumar A, Singh A - Front Pharmacol (2015)

Bottom Line: Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD.These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified.Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University , Chandigarh, India.

ABSTRACT
Neurodegenerative diseases are intricate in nature because of the involvement of the multiple pathophysiological events including mitochondrial dysfunction, neuroinflammation and oxidative stress. Alzheimer's disease (AD) is a neurodegenerative disease explained by extracellular amyloid β deposits, intracellular neurofibrillary tangles and mitochondrial dysfunction. Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD. Mitochondrial dysfunction involves alterations in mitochondrial respiratory enzyme complex activities, oxidative stress, opening of permeability transition pore, and enhanced apoptosis. Various bioenergetics and antioxidants have been tried or under different investigational phase against AD and other neurodegenerative disorders (Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) because of their complex and multiple site of action. These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified. Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.

No MeSH data available.


Related in: MedlinePlus

Mechanism of mitochondrial dysfunction in Alzheimer’s disease. (Aβ-amyloid β, OXPHOS- oxidative phosphorylation, ROS- reative oxygen species, mPTP- mitochondrial permeability transition pore, Cyt C- cytochrome C, Drp1- dynamin—related protein-1, ABAD- amyloid β binding alcohol dehydrogenase, α-KGDH- α-ketoglutarate dehydrogenase complex, PGC-1α- peroxisome proliferator activated receptor-γ-coactivator-1-α). Adopted and modified from Reddy and Beal (2008).
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Figure 1: Mechanism of mitochondrial dysfunction in Alzheimer’s disease. (Aβ-amyloid β, OXPHOS- oxidative phosphorylation, ROS- reative oxygen species, mPTP- mitochondrial permeability transition pore, Cyt C- cytochrome C, Drp1- dynamin—related protein-1, ABAD- amyloid β binding alcohol dehydrogenase, α-KGDH- α-ketoglutarate dehydrogenase complex, PGC-1α- peroxisome proliferator activated receptor-γ-coactivator-1-α). Adopted and modified from Reddy and Beal (2008).

Mentions: As reported earlier, in AD there is abnormal APP metabolism and an excessive Aβ accumulation (Kumar and Singh, 2015). It has been reported that Aβ peptides are present in the neuronal cells as well as in mitochondria (Swerdlow and Khan, 2004). When Aβ peptides accumulates in mitochondria it causes inhibition of mitochondrial respiratory enzyme complex-II and IV, causes decreased production of ATP and an increased production of ROS mitochondrial dysfunction in AD (Figure 1, Rhein et al., 2009; Swerdlow et al., 2010). Accumulation of Aβ peptides also known to reduce activity of enzyme of the tricarboxylic acid (TCA) cycle, α-ketoglutarate dehydrogenase (αKGD), pyruvate dehydrogenase and isocitrate dehydrogenase (Huang et al., 2003; Bubber et al., 2005). It is reported that, Aβ peptides interact with the Aβ binding site known as Aβ binding alcohol dehydrogenase (ABAD) which are present in the mitochondrial membranes and causes mitochondrial dysfunction (Lustbader et al., 2004), abnormal mitochondrial trafficking and decreased mitochondrial movement finally leads to synaptic degeneration (Calkins and Reddy, 2011). Further, Aβ peptide accumulation leads to dysfunctioning of mitochondrial Ca2+ channels, opening of mPTP and enhancement of cytochrome C (CytC) release (Calkins et al., 2011). Moreover, Aβ peptide accumulation inhibits protein import inside the mitochondria, which leads to mutation of mitochondrial DNA (mtDNA) and its damage (Lakatos et al., 2010). Mutations in APP also cause alterations of Ca2+ homeostasis leading to apoptosis (Khan et al., 2000). Accumulation of Aβ peptide and hyperphosphorylation of tau causes increased DRP-1nitrosylation which in turn causes abrupt mitochondrial fission and neurodegeneration (Manczak et al., 2011). Accumulation of soluble Aβ peptide and mutant APP impairs mitochondrial fusion and fission functions, abnormal mitochondrial movement, morphology and degradation of mitochondria (Manczak et al., 2011). Besides, it has also been reported that Aβ peptide accumulation causes abnormal expression of mitochondrial fission (Fis1) and fusion (mfn1/2 and OPA1) proteins which are involved in mitochondrial fission and fusion machinery (Manczak et al., 2011). These impaired dynamics causes decreased clearance of defective mitochondria which further enhanced neurodegeneration (Manczak et al., 2011). It has been studied that Aβ peptides induced hyperphosphorylation of tau causes inhibition of fission protein DRP1 which leads to abnormal mitochondrial elongation (Wang et al., 2008). In another study, Aβ peptides decrease proliferator-activated receptor-γ coactivator-1 α (PGC-1α) expressions, which leads to decreased mitochondrial biogenesis, mitochondrial DNA content (mtDNA) and increased neurodegeneration (McGill and Beal, 2006). Activation of PGC-1α causes increased non-amyloidogenic processing of APP, reduction in Aβ levels leading to increased survival of neuronal cells (McGill and Beal, 2006).


A review on mitochondrial restorative mechanism of antioxidants in Alzheimer's disease and other neurological conditions.

Kumar A, Singh A - Front Pharmacol (2015)

Mechanism of mitochondrial dysfunction in Alzheimer’s disease. (Aβ-amyloid β, OXPHOS- oxidative phosphorylation, ROS- reative oxygen species, mPTP- mitochondrial permeability transition pore, Cyt C- cytochrome C, Drp1- dynamin—related protein-1, ABAD- amyloid β binding alcohol dehydrogenase, α-KGDH- α-ketoglutarate dehydrogenase complex, PGC-1α- peroxisome proliferator activated receptor-γ-coactivator-1-α). Adopted and modified from Reddy and Beal (2008).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585235&req=5

Figure 1: Mechanism of mitochondrial dysfunction in Alzheimer’s disease. (Aβ-amyloid β, OXPHOS- oxidative phosphorylation, ROS- reative oxygen species, mPTP- mitochondrial permeability transition pore, Cyt C- cytochrome C, Drp1- dynamin—related protein-1, ABAD- amyloid β binding alcohol dehydrogenase, α-KGDH- α-ketoglutarate dehydrogenase complex, PGC-1α- peroxisome proliferator activated receptor-γ-coactivator-1-α). Adopted and modified from Reddy and Beal (2008).
Mentions: As reported earlier, in AD there is abnormal APP metabolism and an excessive Aβ accumulation (Kumar and Singh, 2015). It has been reported that Aβ peptides are present in the neuronal cells as well as in mitochondria (Swerdlow and Khan, 2004). When Aβ peptides accumulates in mitochondria it causes inhibition of mitochondrial respiratory enzyme complex-II and IV, causes decreased production of ATP and an increased production of ROS mitochondrial dysfunction in AD (Figure 1, Rhein et al., 2009; Swerdlow et al., 2010). Accumulation of Aβ peptides also known to reduce activity of enzyme of the tricarboxylic acid (TCA) cycle, α-ketoglutarate dehydrogenase (αKGD), pyruvate dehydrogenase and isocitrate dehydrogenase (Huang et al., 2003; Bubber et al., 2005). It is reported that, Aβ peptides interact with the Aβ binding site known as Aβ binding alcohol dehydrogenase (ABAD) which are present in the mitochondrial membranes and causes mitochondrial dysfunction (Lustbader et al., 2004), abnormal mitochondrial trafficking and decreased mitochondrial movement finally leads to synaptic degeneration (Calkins and Reddy, 2011). Further, Aβ peptide accumulation leads to dysfunctioning of mitochondrial Ca2+ channels, opening of mPTP and enhancement of cytochrome C (CytC) release (Calkins et al., 2011). Moreover, Aβ peptide accumulation inhibits protein import inside the mitochondria, which leads to mutation of mitochondrial DNA (mtDNA) and its damage (Lakatos et al., 2010). Mutations in APP also cause alterations of Ca2+ homeostasis leading to apoptosis (Khan et al., 2000). Accumulation of Aβ peptide and hyperphosphorylation of tau causes increased DRP-1nitrosylation which in turn causes abrupt mitochondrial fission and neurodegeneration (Manczak et al., 2011). Accumulation of soluble Aβ peptide and mutant APP impairs mitochondrial fusion and fission functions, abnormal mitochondrial movement, morphology and degradation of mitochondria (Manczak et al., 2011). Besides, it has also been reported that Aβ peptide accumulation causes abnormal expression of mitochondrial fission (Fis1) and fusion (mfn1/2 and OPA1) proteins which are involved in mitochondrial fission and fusion machinery (Manczak et al., 2011). These impaired dynamics causes decreased clearance of defective mitochondria which further enhanced neurodegeneration (Manczak et al., 2011). It has been studied that Aβ peptides induced hyperphosphorylation of tau causes inhibition of fission protein DRP1 which leads to abnormal mitochondrial elongation (Wang et al., 2008). In another study, Aβ peptides decrease proliferator-activated receptor-γ coactivator-1 α (PGC-1α) expressions, which leads to decreased mitochondrial biogenesis, mitochondrial DNA content (mtDNA) and increased neurodegeneration (McGill and Beal, 2006). Activation of PGC-1α causes increased non-amyloidogenic processing of APP, reduction in Aβ levels leading to increased survival of neuronal cells (McGill and Beal, 2006).

Bottom Line: Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD.These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified.Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology Division, University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Study, Panjab University , Chandigarh, India.

ABSTRACT
Neurodegenerative diseases are intricate in nature because of the involvement of the multiple pathophysiological events including mitochondrial dysfunction, neuroinflammation and oxidative stress. Alzheimer's disease (AD) is a neurodegenerative disease explained by extracellular amyloid β deposits, intracellular neurofibrillary tangles and mitochondrial dysfunction. Increasing evidence has indicated that mitochondrial dysfunction displays significant role in the pathophysiological processes of AD. Mitochondrial dysfunction involves alterations in mitochondrial respiratory enzyme complex activities, oxidative stress, opening of permeability transition pore, and enhanced apoptosis. Various bioenergetics and antioxidants have been tried or under different investigational phase against AD and other neurodegenerative disorders (Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis) because of their complex and multiple site of action. These mitochondrial-targeting bioenergetics and antioxidant compounds such as coenzyme Q10, idebenone, creatine, mitoQ, mitovitE, MitoTEMPOL, latrepirdine, methylene blue, triterpenoids, SS peptides, curcumin, Ginkgo biloba, and omega-3 polyunsaturated fatty acids with potential efficacy in AD have been identified. Present review is intent to discuss mitochondrial restorative mechanisms of these bioenergetics and antioxidants as a potential alternative drug strategy for effective management of AD.

No MeSH data available.


Related in: MedlinePlus