The pathogenesis of neurodegenerative disorders

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Most individuals with complex V deficit had clinical onset in the neonatal period with multiorgan failure or severe brain damage leading to a high mortality, such as cardiomyopathy and neuromuscular disorders Mitochondrial biogenesis assumes a critical part to keep mitochondrial homeostasis during the mitochondria life cycle and finally meet the physiological demands of eukaryotic cells Moreover, strong research evidence recommends a probable reduction in ROS production by the biogenesis of a significant density of functional mitochondria As a highly regulated process, mitochondrial biogenesis requires the participation of both the mitochondrial and nuclear genomes and happens frequently in healthy cells that continually divide and fuse with each other, while in unhealthy cells, division fission is leading and after cerebral insults, the mitochondrial network fragments Increased biogenesis is compatible with the mtDNA copy number and enhanced mitochondrial gene expression.

As mitochondria are not synthesized from the beginning, they should proliferate from the ones already existing to keep biogenesis 6. Their biogenesis appears to be controlled via several processes, including 1 synthesis of outer and inner mitochondrial membranes, 2 synthesis of mitochondrial proteins, 3 synthesis and import of proteins encoded by the nuclear genome, 4 lipid import, 5 oxidative phosphorylation, 6 replication of mtDNA, and 7 mitochondrial fusion and fission 6 , Usually, alterations in physiological state including enhanced rates of ATP consumption activate mitochondrial biogenesis for approaching the existing cells capacity to generate it.

Multiple investigations offer that disruption of mitochondrial function considered as a critical cause in the pathophysiology of numerous neurological disorders, and adaptive mitochondrial biogenesis has been studied in the nervous system It is highlighted that impaired mitochondrial biogenesis potentially contributes to the mitochondrial dysfunction and has a significant role in the pathogenesis of the neurodegenerative diseases. Likewise, it should be noted that genes encoding proteins which play a key role in mitochondrial biogenesis are linked with those diseases Taken together, induction or improvement of mitochondrial biogenesis may be considered as a novel therapeutic target and confirm a modern neuroprotective approach for most of diseases such as neurodegenerative diseases including AD, PD, HD, and ALS in the near future 92 Figure 3.

Dysregulation of protein homeostasis happens over time via stress induced by the accumulation of ROS and mutations in the mitochondrial genome introduced during replication Major challenges in cell biology are recognizing all the proteins in this organelle and understanding how they involved in pathways The dynamics of mitochondrial function and biogenesis is a complex interplay of cellular and molecular processes that ultimately shape bioenergetics capacity. Mitochondrial mass, by itself, represents the net balance between rates of biogenesis and degradation Mitochondrial biogenesis is dependent on different signaling cascades and transcriptional complexes that promote the formation and assembly of mitochondria.

It is a process that is heavily dependent on timely and coordinated transcriptional control of genes encoding for mitochondrial proteins Also, the nuclear regulation mechanisms cause the tissue induction and signal specific subsets of genes that serve particular functions. It has effect on the activity or expression of numerous genes in a range of signaling networks, including insulin sensitivity regulation, cell fates, immune responses, fatty acid oxidation, glucose homeostasis, cardiovascular integrity, and redox balance Mitochondrial biogenesis involves other transcription factors such as sirtuins.

Sirtuins can influence the progression of neurodegenerative disorders by modulating transcription factor activity - Furthermore, SIRT3 which interacts with mitochondrial complex I is another novel therapeutic target for neurodegenerative diseases Antioxidants protect neurons against mitochondrial functional and structural abnormalities, oxidative damage, and mutant proteins In addition, administration of MitoQ could extend cell survival and ameliorate motor performance and brain atrophy in a transgenic mouse model of HD Likewise, SS31 may use for HD therapy by promoting mitochondrial function and neuronal viability Additionally, SS31 is a novel therapeutic approach to treat neuronal damage induced by oxidative stress in a mouse model of ALS.

It targets the ROS production at the inner mitochondrial membrane and prevents further mitochondrial damage AD is the most common neurodegenerative disorder marked by progressive loss of memory, characterized by the increased presence of extraneuronal amyloid plaques derived from the proteolytic processing of the amyloid precursor protein APP and intraneuronal neurofibrillary tangles NFTs made from hyperphosphorylated tau protein pTau in the brain. Recent evidence indicates that mitochondrial dysfunction is a noticeable and early feature of AD with lower energy metabolism as one of the best known primary abnormalities in this disease Multiple documents recommended that mitochondrial dysfunction, particularly, deficiencies in mitochondrial respiratory chain complex I has been considered a potential unifying factor in pathogenesis of the neurodegenerative disorders including AD 56 , , Hyperphosphorylated forms of tau selectively impair complex I, lead to increased ROS levels, and result in reduced levels of ATP - Clinical and experimental observations suggest that complex I inhibition could contribute to pathogenic mechanisms in some sporadic tauopathies 74 Figure 2.

Neurodegeneration

Furthermore, reduced activity of mitochondrial enzymes, such as complex III, has been reported. It has been stated that a reduction in complex IV activity in the brain associated with aging 72 Figure 2. Likewise, it is believed that glutamate excitotoxicity happens in chronic neurodegenerative diseases such as AD 47 , 72 , Insufficient control over glutamate release as a result of mitochondrial complex IV and III deficiency can lead to neuronal cell death.

Glutamate release happens mainly through reversal of glutamate transporters of plasma membrane during severe energy stress. The status of this vital feature of mitochondrial function and life in AD is not clear 20 , Upregulated ETC.

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Possibly, in different stages of disease, neurons exhibit different forms of mitochondrial biogenesis These events close in on tau protein aggregation and autophagic dysfunction and then lead to neurodegeneration and cell death in AD Figure 4. Expression levels of these genes significantly reduced in both AD hippocampal cells and tissues, proposing a decreased mitochondrial biogenesis It locates on chromosome 10, on which many genes have been reported to be associated with sporadic AD Overall, this data demonstrated mitochondrial biogenesis induction decreases mitochondria dysfunction.

Based on data mentioned above, the impaired mitochondrial biogenesis has been suggested as underlying factor in mitochondrial dysfunction in AD and increasing mitochondrial biogenesis may represent a possible pharmacologic strategies for the AD treatment However, the cellular mechanisms that result in cell death in the nigrostriatal system in PD are still unclear , , it is generally accepted that the causes of PD are mainly mitochondrial dysfunction, oxidative stress, chronic inflammation, aberrant protein folding, and abnormal protein aggregation 89 , , The significant reduction in ATP and phosphocreatine PCr in the putamen and the significant reduction in ATP in the midbrain as high energy metabolites are indicative of mitochondrial dysfunction in the mesostriatal dopaminergic neurons in early and advanced PD 21 ; however, reduction in the ATP production is not just the outcome of mitochondrial dysfunction.

Neurodegenerative disease: Corinne Lasmezas at TEDxJupiter

In addition, there are other potentially deleterious events such as enhanced formation of free radicals, induction of permeability transition, impaired intracellular calcium homeostasis, and oxidative stress, which in predispose affected cells to necrosis or apoptosis depending on the rate of consumption and depletion of ATP 55 , Prohibition of mitochondrial respiratory chain may result in incomplete consumption of O2, decreased of ATP, and increased free radical formation.

Free radicals directly inhibit the respiratory chain of mitochondria, which can cause a detrimental cycle that results in oxidative cell damage Several mutations in mitochondrial proteins encoded by nuclear and mitochondrial genes were linked with idiopathic and familial types of PD In this regard, several postmortem studies have shown a meaningful decline in the mitochondrial complex I activity as well as coenzyme Q10, ubiquinone, and also complex IV in the substantia nigra of PD brains - Figure 2.

Complex I deficit is the most common cause of rare diseases of respiratory chain 14 as well as endogenous and environmental oxidative stressors underlying mitochondrial dysfunction observed in neurodegenerative diseases including PD 89 , The latest study revealed that activity of complex I is decreased in postmortem brain tissue of patients with PD as a consequence of oxidative damage that leads to instability and loss through degradation of at least one subunit Particularly, loss of activity of complex I at the mitochondrial ETC.

In animal models of PD e. Interestingly, parkin and PINK1 have been implicated in regulating mitochondrial biogenesis Parkin has a part in mitochondrial biogenesis , by controlling both replication and transcription of mtDNA in proliferating cells. It increases mitochondrial replication, expressions, and transcription of respiratory chain complexes On the other hand, PINK1 is processed by healthy mitochondria and released to trigger neuron differentiation They showed their dysfunction was involved in sporadic types of PD.


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In addition, mutation of LRRK2 may result in abnormal phosphorylation of mitochondrial proteins which induces apoptotic cell death Figure 5. Moreover, there is an association between TFAM and parkin. Additionally, involvement of TFAM as a multifunctional mtDNA metabolism regulator in pathogenesis of PD in vitro and in vivo models of PD directly and indirectly confirmed via increase in mitochondrial respiratory functions and protection from oxidative stress Likewise, it has been suggested that AMPK activation as a therapeutic approach may promote neuroprotection in PD by mediating mitochondrial biogenesis Indeed, the pathway of mitochondrial biogenesis has come as a possible healing target for PD.

HD is an inherited and an autosomal dominant disorder characterized by psychiatric disturbances, cognitive deterioration, and motor impairment.


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Mitochondrial dysfunction is strongly associated with the pathogenesis of HD - Another potential cause of mitochondrial dysfunction in HD brains is the toxic effects of mutant Htt that result in those changes in mitochondrial complex activities In the postmortem on patients with HD, the main hypothesis behind abnormalities in the mitochondrial respiratory chain reveals that they are indirectly or directly caused by the toxic mHtt expression 59 , Complex III inhibitors selectively promoted the accumulation of Htt aggregates.

As other respiratory inhibitors had no considerable effect on the formation of Htt aggregates, the depletion of ATP does not simply explain the effects of complex III inhibitors 71 , Likewise, AMPK activation induces neuroprotection in HD through promoting mitochondrial biogenesis and elevating cell survival These results propose that the biogenesis pathway of mitochondria can be a potential novel therapeutic target for HD treatment.

Disease in humans and rodent models initiates with muscle denervation and muscle atrophy following denervation, each arising from degeneration and selective loss of motor neurons in the spinal cord as well as brain Morphological and biochemical mitochondrial abnormalities including a reduction in mtDNA copy number and deficiencies in activity of respiratory chain were confirmed in postmortem spinal cords of patients with ALS It suggests that mitochondrial dysfunction in skeletal muscle plays key roles in the pathogenesis of ALS Several previous studies reported changes in mitochondrial ETC.

For instance, increased activity of complex I found in postmortem brain tissue may indicate a compensatory incident against the deficit of complex IV enzymes encoded by mtDNA which seen in some patients with ALS. Moreover, higher levels of oxidized ETC. Menzies et al. Because neuroinflammatory pathway is one of the hallmarks of ALS, thus, neuroinflammation blockage may have a therapeutic effect on patients with ALS 64 , As highly dynamic organelles, mitochondria have crucial roles in cell survival as well as cell death 1 , 2 and able to alter their morphology, number, and function in reaction to stressors and physiological conditions 2.

The morphology of mitochondria is controlled by repetitive cycles of mitochondrial fusion and fission machinery which are central to mitochondrial dynamics Altered mitochondrial dynamics as well as mDNA mutations 8 , gene mutations 9 , impaired transcription contribute to mitochondrial dysfunction 10 which results in the pathogenesis of several diseases 3 , 11 , Dysfunction and abnormality in mitochondrial dynamics, such as reduced mitochondrial mixing fusion and increased mitochondrial fragmentation fission , are important factors related to the mitochondrial dysfunction, cell death in aging 19 , and neurodegenerative diseases, including AD 20 , PD 21 , HD 22 , and ALS Mitochondrial dysfunction is reflected by mtDNA damage and decrease in mitochondrial function, mtRNA transcripts, and protein synthesis Mitochondrial functions are changed in brains of individuals with specific neurodegenerative disorders 70 , In addition, dysfunction of ETC.

Several lines of evidence demonstrate that mitochondrial biogenesis has a vital role in maintaining mitochondrial homeostasis to meet the physiological requirements of eukaryotic cells Accordingly, the impaired mitochondrial biogenesis is associated with the mitochondrial dysfunction and has a significant role in the pathogenesis of the neurodegenerative disorders Overall, this data demonstrated induction or improvement of mitochondrial biogenesis alleviates mitochondrial dysfunction and may confirm a modern neuroprotective approach in the near future Volume 23 , Issue 1.

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Review Open Access. Abolhassan Ahmadiani Corresponding Author E-mail address: aahmadiani yahoo. The first two authors contributed equally to this work. Tools Request permission Export citation Add to favorites Track citation. Share Give access Share full text access. Share full text access. Please review our Terms and Conditions of Use and check box below to share full-text version of article. Summary Neurodegenerative diseases are a heterogeneous group of disorders that are incurable and characterized by the progressive degeneration of the function and structure of the central nervous system CNS for reasons that are not yet understood.

Introduction Mitochondria play important roles in cell respiratory processes, metabolism, energy production, intracellular signaling, free radical production, and apoptosis 1 , 2. Mitochondrial Biology and Dynamics As dynamic organelles, mitochondria are vital for cellular death, life, and differentiation. Figure 1 Open in figure viewer PowerPoint.

Mitochondrial Dysfunction and Neurodegenerative Diseases As organelles of eukaryotic cells, mitochondria have several functions, such as synthesis of ATP through energy transduction. Mitochondrial Complexes and Neurodegenerative Diseases Mitochondria are complex organelles whose dysfunction causes a broad range of diseases Figure 2 Open in figure viewer PowerPoint.

Mitochondrial Biogenesis and Neurodegenerative Diseases Mitochondrial biogenesis assumes a critical part to keep mitochondrial homeostasis during the mitochondria life cycle and finally meet the physiological demands of eukaryotic cells Cookson MR. The biochemistry of Parkinson's disease.

Oxidative stress and the pathogenesis of neurodegenerative disorders.

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Pathology of Neurodegenerative Diseases

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