Reappraisal Of Metabolic Dysfunction in Neurodegeneration: Focus On Mitochondrial Function And Calcium Signaling Part 5

Oxidative stress

Impaired metabolism in NDDs is linked to the production of RNS and ROS. Multiple hallmarks of NDDs including mitochondrial dysfunction, misfolded proteins, and inflammation are known consequences of elevated RNS/ROS production [274]. 

Metabolism is a chemical process in the human body that controls the balance of many life functions. When metabolism is impaired, it may affect a person's health and physical function. However, when it comes to memory, impaired metabolism can only hurt it in severe cases.

In most cases, the impact of impaired metabolism on memory is not obvious. We can only see this relationship when there is a significant change in metabolism. For example, metabolic disorders often lead to neuronal damage, which may affect a person's memory and cognitive ability.

However, we don't want to think about this issue negatively. Compared with impaired metabolism and memory, we should think more about how to improve metabolism and memory. Here are some effective suggestions:

First, pay attention to choosing healthy foods in your diet, such as eating more vegetables, fruits, and grains. This can help the body absorb more nutrients and promote the normal functioning of metabolism.

Second, get enough sleep. Lack of sleep may affect metabolism and also reduce memory and cognitive ability.

Third, do proper exercise. Moderate exercise can increase metabolic rate, promote cardiopulmonary health, and also improve physical and brain function.

Finally, memory is a plastic ability. Through continuous learning and training, we can improve our memory and cognitive ability. Although impaired metabolism may hurt us, as long as we improve it in the right way, we can still live a healthy, happy, and fulfilling life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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The relationship between mitochondrial dysfunction, aberrant ROS signaling, and neurodegeneration has been reviewed elsewhere [275]. Elevated RNS production in NDDs is thought to occur as a result of elevated I Ca2+ concentration, which increases nitric oxide (NO) production by neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS). 

Excess NO in turn promotes mitochondrial dysfunction, which can exacerbate bioenergetic compromise and accelerate neurodegeneration [276]. 

This may occur through reversible S-nitrosylation of cysteine residues on proteins important for mitochondrial homeostasis such as Parkin and Drp1, as well as proteins such as Protein disulfide isomerase (PDI) that help to ensure proper protein folding (reviewed in [276]). 

Nitric oxide can also react with superoxide to form peroxynitrite, which irreversibly modifies tyrosine residues via tyrosine nitration [277]. Nitric oxide inhibits numerous proteins involved in metabolism, providing a mechanistic link between elevated I Ca2+ levels and altered metabolism in NDDs. 

NO attenuates glycolysis and fatty acid oxidation via inhibitory S-nitrosylation of key enzymes in these pathways such as GAPDH [274, 276]. Such effects would impede metabolism by limiting carbon input into the TCA cycle. 

Furthermore, S-nitrosylation of the TCA cycle enzymes citrate synthase, aconitase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinyl-CoA synthetase, succinate dehydrogenase, and malate dehydrogenase has been observed [278, 279] and is often inhibitory [280, 281]. 

In particular, isocitrate dehydrogenase is a rate-limiting step within the TCA cycle [282], and inhibitory S-nitrosylation of this enzyme could limit TCA cycle flux and overall mitochondrial metabolism. Downstream of the TCA cycle, S-nitrosylation can inhibit ETC complexes I [283–285], IV [286], and V (ATP synthase) [287]. Tyrosine nitration also inhibits all ETC complexes [288, 289]. 

Thus, excessive RNS production in NDDs can impair mitochondrial metabolism by direct action on multiple targets and pathways. Much remains to be determined regarding the specific role of mitochondrial RNS stress in the progression of NDDs. 

Some recent studies support a link between increased NO production and altered mitochondrial activity. Induced pluripotent stem cells expressing the A53T mutation in α-synuclein, which causes familial PD, exhibit decreased mitochondrial respiration that is attributed to aberrant S-nitrosylation of the transcription factor MEF2C, which leads to impaired PGC1α expression [290]. 

A similar effect of abnormal MEF2 S-nitrosylation is associated with neurodegeneration in AD [291]. Any initial impairment of mitochondrial respiratory activity can trigger excess ROS and RNS production, leading to further oxidative or nitrosative stress [112, 292, 293] that feeds back to impair mitochondrial metabolism. 

Fitting with this notion, increased ROS production by the ETC is indeed observed in neurodegeneration [274, 294]. While increased ROS production in NDDs may be a direct consequence of increased mCa2+ concentration, it is tempting to speculate that increased cellular NO production may also contribute to this effect by initiating ETC dysfunction. 

Finally, it is worth noting that data also exist supporting a neuro-protective role for nitric oxide in some NDDs. 

As reviewed by Calabrese et al., within the context of normal physiology, NO can exert neuroprotective effects via several mechanisms including stimulation of pro-survival Akt and cyclic-AMP-responsive-element binding protein (CREB) signaling pathways, S-nitrosylation of the NMDA receptor to limit cellular Ca2+ uptake and excitotoxicity, inhibitory S-nitrosylation of caspases, and the upregulation of heme oxygenase 1 to stimulate cellular antioxidant production [295].

Transcriptional regulation

Several observations indicate that changes in transcriptional programs contribute to altered metabolism in NDDs. The expression of key energy and metabolism genes, such as components of the ETC, is reduced at both the mRNA and protein levels in autopsied AD brains [262]. 

Furthermore, transcriptional repression of PGC-1α, a transcription coactivator with a central role in mitochondrial biogenesis, is observed in mouse models of HD [270]. These examples illustrate a general phenomenon, common to NDDs, of decreased transcription of genes involved in mitochondrial and oxidative metabolism [296]. 

Much work remains to determine the mechanisms responsible, but some evidence supports the notion that restoration of transcription is beneficial in NDDs. Specifically, activation of transcription factors including CREB, NF-κB, and NRF2 is protective in murine models of these diseases (reviewed in [174, 297]). 

It is interesting to note that exercise and aerobic activity can activate some of these neuroprotective transcription factors [174]. Thus, an interesting question is whether impaired locomotion and reduced physical activity in some NDDs diminish the activation of beneficial transcriptional programs, and so drive further transcriptional and metabolic defects. 

One example of how metabolic gene transcription may become disrupted in NDDs is by impairment of Peroxisome proliferator-activated receptor (PPAR)-γ co-activator 1α (PGC-1α). 

As reviewed elsewhere [298], PGC-1α is activated by AMPK during times of metabolic stress, and in concert with the transcription factor NRF-1 increases the expression of nuclear genes involved in mitochondrial biogenesis [299, 300]. 

PGC-1α also upregulates mitophagic genes [301, 302] and thus can impact mitochondrial quality control, turnover, and net mitochondrial content. NDDs are generally associated with reduced expression of PGC-1α, which likely represents a common mechanism for metabolic impairment in these diseases. 

Reduced expression of PGC-1α is observed in Alzheimer's patients and the TG2576 mouse model of AD (transgenic expression of the APP Swedish mutation) [303]. 

Mutant forms of presenilin associated with familial AD are associated with reduced PGC-1α expression [304], while in vitro restoration of PGC-1α in AD cell lines improves overall function [303, 305]. 

This suggests that diminished PGC-1α function, and perhaps subsequent mitochondrial impairment, contributes to AD pathogenesis. Similar evidence for reduced PGC-1α activity is reported in Parkinson's disease. 

PD patients exhibit reduced expression of PGC-1α target genes, such as components of the ETC [306]. In cell and animal models, loss of PGC-1α increases susceptibility to PD [307, 308], while overexpression of PGC-1α protects against neuronal death [306, 309]. Recent work indicates that the protein PARIS (ZFN746 gene), which is normally ubiquitinated by Parkin, can repress PGC-1α expression [310]. 

Thus, loss of Parkin in PD may elicit the accumulation of PARIS and downregulation of PGC-1α. In support of this notion, stereotactic injection of recombinant PARIS into the substantia nigra of mice causes neuronal death, but this is prevented by simultaneous injection of exogenous recombinant PGC-1α [310]. Together, these data support the idea that downregulation of PGC-1α is secondary to causative NDD gene mutations, but reduces mitochondria content and disrupts quality control, thereby furthering neuronal dysfunction and disease progression. 

Huntington's disease is more closely linked to defects in PGC-1α signaling than other NDDs. Deletion of PGC-1α in mice causes neurodegeneration and recapitulates symptoms of HD [311, 312], and induction of PGC-1α can rescue HD symptoms in mice[313]. 

Predictably, HD patients and mouse models display reduced PGC-1α expression and reduced expression of mitochondrial genes [314]. These features can be explained by the binding of mutant huntingtin protein to the PGC-1α promotor, which represses PGC-1α transcription [270]. 

Deletion of PGC-1α in HD mouse models exacerbates neurodegeneration, whereas striatal overexpression of PGC-1α is sufficient to protect against neuronal atrophy [270]. Overall, PGC-1α likely plays a central role in the progression of NDDs, and so is an attractive therapeutic target.

Insulin signaling

Multiple studies support an association between altered insulin signaling and NDDs. Altered glucose metabolism is common in both AD and PD [174, 315], and both of these diseases are linked to type 2 diabetes [316–318]. 

Indeed, many of the same risk factors for developing obesity or diabetes (lack of physical activity, excess calorie consumption, etc.) predispose to the development of NDDs, especially AD and PD [319]. 

Variants in insulin signaling pathway genes, such as AKT [320] and GSK3β [321], increase the risk for PD. Thus, diminished insulin responsiveness and impaired glucose utilization may contribute to impaired neuronal metabolism in some NDD patients. This represents further evidence that a decline in metabolic health may initiate NDD development. 

The glucose transporters GLUT1 (insulin-insensitive) and GLUT3 (insulin-sensitive) are decreased in AD brains [322, 323]. These changes may limit brain glucose uptake and contribute to cognitive impairments in AD [324]. 

A report that reduces GLUT1 expression in AD mouse models and worsens amyloid burden, neurodegeneration, and cognitive function [325] supports this idea. Additionally, insulin deficiency favors phosphorylation of tau and the development of neurofibrillary pathology [326], reinforcing the notion that disrupted insulin signaling promotes AD progression. 

In agreement, impaired glucose metabolism is a well-documented feature of PD brains [174], and lower levels of pyruvate oxidation are observed in PD fibroblasts [111]. These effects are recapitulated in animal models of PD [327–329] and may reflect impaired insulin signaling. 

Activation of AKT, a classical downstream target of insulin signaling, is reduced in the substantia nigra of PD brains and in in vitro cellular models of PD [330–333]. 

Genetic mutations in proteins linked to PD, including DJ-1 and PINK1, are also associated with diminished AKT signaling [334] and provide further evidence for altered insulin responsiveness in this disease. To the extent that altered insulin/AKT signaling limits carbon (i.e., glucose) metabolism within neurons, it would limit fuel input to the TCA cycle and decrease mitochondrial ATP production [335]. 

Limited mitochondrial energetics may be just one consequence of diminished glucose uptake or utilization in PD. Dopaminergic neurons do not tolerate glucose starvation [336], and glucose deprivation in vitro is sufficient to cause α-synuclein aggregation and death of dopaminergic neurons [337]. 

These data support the idea that impaired glucose utilization is an early driver of PD pathology and may lead not only to impaired mitochondrial metabolism but also to amyloidosis and neuronal death. 

Altered glucose metabolism is an early feature of HD, even though the expression of glucose transporters is normal in the initial stages of the disease [153, 338, 339]. 

This defect is explained by diminished localization of the glucose transporters at the neuronal plasma membrane [340]. Interestingly, defects in metabolism are observed before striatal atrophy, and reduced glucose metabolism strongly correlates with HD progression [341–343]. 

The funding that increases the expression of GLUT3 or enzymes involved in glucose metabolism can protect against the progression of HD [344, 345] strengthens this view.

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