Sirtuins Modulation: A Promising Strategy For HIV-Associated Neurocognitive Impairments Part 3

5.4. SIRT3

The energy metabolism pathways carried out in the mitochondria, such as the tricarboxylic acid pathway and ATP generation, are influenced by SIRT3 [116,117]. Therefore, SIRT3 is related to aging, cancer, cardiac dysfunction, and neurodegenerative diseases [117]. 

In recent years, more and more studies have shown that mitochondria are closely related to memory. Mitochondria are an important organelle in cells. Their function is not only to provide energy for cells, but also to participate in a variety of physiological processes such as cell death, anti-oxidation, and signal transduction.

The latest research results show that abnormal mitochondrial function can lead to many neurological diseases, such as Alzheimer's disease and Parkinson's disease. These diseases cause serious damage to the human nervous system and affect people's thinking ability and memory.

The relationship between mitochondria and memory has been confirmed in many studies. Experiments have shown that maintaining the health of mitochondria can improve people's memory. Scientists have found that there is a close connection between mitochondria and neurons. Mitochondria play an important role in maintaining the normal function of neurons in nerve cells, and can also help our memory become sharper.

Therefore, we can improve the function of mitochondria by maintaining good living habits and eating habits to maintain our memory. To maintain healthy mitochondrial function, we need to participate in more sports, eat a reasonable diet, and ensure adequate sleep. At the same time, the state of long-term stress can cause mitochondria to overreact and cause nerve cell damage, so we need to control our emotions and try not to suppress them too much.

In short, the relationship between mitochondria and memory is inseparable. Scientists' research shows that the health of mitochondria directly affects our nervous system, affecting our thinking and memory. We should take a series of measures to ensure the healthy function of mitochondria, thereby enhancing our memory and cognitive abilities. It can be seen that we need to improve our memory, and Cistanche can significantly improve memory because it 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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SIRT3 is the main sirtuin in the mitochondria, despite evidence that SIRT4 and SIRT5 are also present in this organelle. In addition, SIRT3 acts under oxidative stress, and it can regulate mitochondrial biogenesis, autophagy/mitophagy, and apoptosis in diverse cell types [116].
5.4.1. SIRT3 and Antioxidant Response

Overexpression of SIRT3 reduces ROS in MEFs [118] and cardiomyocytes by upregulating gene expression of manganese superoxide dismutase (MnSOD) and by deacetylation of FOXO3a and activating glutathione pathway [119–121]. 

Catalytic inactivated SIRT3 or SIRT3-/- cells showed disruption of the GSH: GSSG ratio [119,120]. This alteration could be linked to SIRT3-mediated deacetylation of isocitrate dehydrogenase 2 (IDH2), which is a source of the NADP required in GHS/GSSG reactions [120]. 

Furthermore, depletion of SIRT3 is accompanied by loss of the mitochondria membrane potential in MEFs [118]. The evidence reveals that SIRT3 is involved in ROS mitigation in the cell through the regulation of gene expression and activation of proteins of the antioxidant response.

5.4.2. SIRT3 and Mitochondrial Biogenesis and mtDNA Integrity

PGC1α is a pivotal player in mitochondrial biogenesis, hence it regulates the expression of NFR1 that, in turn, enhances the transcription of TFAM, thereby promoting the production of mitochondrial proteins [28]. SIRT3 silencing downregulates the gene expression of PGC1α, as well as NRF1, TFAM, and SIRT1 [122], which are PGC1α activators [28]. 

On the other hand, SIRT3 protects mtDNA through the regulation of OGG1 and Lon proteins [123,124]. OGG1 repairs DNA, eliminating oxidized guanine 8-oxoG caused by ROS. SIRT3 deacetylates OGG1 to induce its activity since the silencing of SIRT3 irradiated cells exhibited an increase of 8-oxoG compared to SIRT3 Wt [123]. 

Indeed, it was observed that SIRT3 deacetylation prevents OGG1 degradation by calpain, a calcium-dependent nonlysosomal cysteine protease [123]. Mitochondria metabolism not only depends on OGG1 repair activity but also the replicative events of mtDNA. Lon, a mitochondrial protease, is involved in nonfunctional protein degradation and mtDNA preservation and replication, through the regulation of TFAM [125]. There is evidence indicating that Lon is deacetylated by SIRT3 in breast cancer cell lines [124]. 

Accumulating evidence suggests that SIRT3 modulates mitochondria biogenesis in a transcriptional manner and modulates the stability of mitochondrial proteins required for the maintenance of mtDNA.

5.4.3. SIRT3 and Mitophagy

As discussed before, mitochondria dynamics and mitophagy are linked through mitochondria fission-fusion events. OPA1, an elemental protein in fusion processes, has been related to mtDNA copy number. It was reported that SIRT3 induces the GTPase activity of OPA1 via its deacetylation [118], promoting mitochondria fusion, and modulating their morphology and the genetic amount in the mitochondria network. 

When mitochondria do not recover from damage, mitophagy signaling is activated [68]. There are reports that SIRT3 upregulated mitophagy key proteins, such as parkin, under stress conditions [126]. 

Indeed, it was determined that SIRT3 physically interacts with PINK1 and parkin and that its overexpression reduced the amount of acetylation of these proteins [127]. 

Additionally, it was suggested that the activation of mitophagy by stressors is mediated through the deacetylation of FOXO3a [126]. In SIRT3-/- mouse myocardial cells, impairment of Parkin-mediated mitophagy was detected due to the increase of the complex p53/parkin, which avoids parkin mitochondrial translocation [128]. 

In addition, it has been reported that the N-terminal of SIRT3 interacts with p53 [86]. Furthermore, overexpression of SIRT3 in a PD model increases LC3II and Beclin 1 expression, indicating autophagosome formation, also confirmed by microscopy. The autophagy SIRT3-mediated activation is through LKB1/AMPK/mTOR [129]. 

Collectively, these data imply that SIRT3 activates autophagy/mitophagy to rescue cells from apoptosis; hence, SIRT3 overexpression can abrogate apoptosis via deacetylation of mitochondria p53 [86].

5.4.4. SIRT3 and Tat

In microglia, Tat downregulates the expression of SIRT3 and protein levels of superoxide dismutase-2 (SOD2), and of CAT accompanied by SIRT3 low enzymatic activity. Of note, Thangaraj et al. [29] found that the expression of SIRT4 and SIRT5 was not altered, thus confirming that Tat modulates only SIRT3, causing an oxidative environment in the cells. 

However, overexpression of SIRT3 inhibited the Tat-induced dysregulation in microglia, including abrogation of expression of proinflammatory cytokines [29]. According to the data, activation of SIRT3 must be included as a possible pathway for future investigations focused on preventing and ameliorating the effects of Tat-induced neurodegeneration.

6. SIRT Modulation

6.1. Inhibitors

As a result of the role of SIRTs in many cellular processes related to diseases such as cancer and metabolic disorders, a variety of molecules have been studied as SIRT inhibitors. Sirtinol, suramin, and EX-527 have shown SIRT inhibition activity [78]. 

Among the inhibitors for SIRT3 are the thieno [3,2-d] pyrimidine-6-carboxamide derivatives that have been demonstrated to inhibit SIRT1 as well [79]. Most of the inhibitors interact with SIRTs in an active, cleft-binding manner [79], meaning that the catalytic site is no longer available during this interaction. Nevertheless, some molecules act via a different mechanism, such as the case of SirReals or Sirtuin rearranging ligands that are considered allosteric inhibitors of SIRT2 and allow for the binding of NAD+. AGK2 is an inhibitor of SIRT2 with neuroprotective results, from reduced cell death and ROS to decreased inflammation [103]. 

Not only small molecules are being studied as SIRTs inhibitors, but also pseudo peptides are the target of peptide-based drug design studies [79]. The suramin, used in the treatment of onchocerciasis and trypanosomiasis, is an inhibitor of SIRT1, SIRT2, and SIRT5 [79]. It has also been investigated as HIV treatment without a beneficial outcome [130]. 

The use of inhibitors to treat HIV infection was postulated in the early years of research because it was found that Tat requires K50 deacetylation for viral transactivation and that it was SIRT1-dependent. 

Nonetheless, later works indicated that viral protein Tat reduces the deacetylation activity of SIRT1, its gene expression, and protein levels in vitro [131] and induces SIRT1 post-transcriptional silencing mediated by miRNA-34a and miRNA-138 [132]. These findings propose a particular requirement at different stages of infection, and because of the cART, viral transcript is controlled, so inhibition of SIRTs could lead to concomitant neurodegeneration.

6.2. Activators

SIRT activation promotes cardio and neuroprotection in several conditions such as myocardial ischemia [133], atherosclerosis [134], cardiac hypertrophy [135], Huntington's disease [98,136], PD [137], and AD [138]. 

Nowadays, there are two approaches to active SIRTs. One is to use natural or synthetic compounds to increase expression or their deacetylation activity. Another perspective is to boost the availability of NAD+ through its precursors. Here, we briefly describe the mechanisms of these xenobiotics to encounter cell stressors, and they are summarized in Table 1.

6.2.1. Polyphenols

The molecule of RV was shown to be an activator of SIRT1 [79,139,142,167]. It has been reported that RV ameliorates ROS under oxidative stress [142,143] and inflammatory conditions [139]. It was reported that RV also increases the expression of SIRT3; hence, it activates SIRT1, which in turn deacetylates PGC1a. 

This transcription factor is influenced by RV to bind to the SIRT3 promoter in neurons exposed to high concentrations of manganese [142]. The data suggest that RV rescues cell integrity by not only enhancing mitochondrial biogenesis due to SIRT1-mediated deacetylation of PGC1a and SIRT3-mediated deacetylation of TFAM [142] but also by inducing mitophagy, as is confirmed by the increase of proteins such as PINK1 and parkin in cardiac injury [106]. Furthermore, in Pb-exposed rats, RV was shown to improve spatial learning memory accompanied by cell proliferation and reduction of neuronal apoptosis [141]. 

As mentioned before, Tat can inhibit SIRT1 activity. Interestingly, high concentrations of RV have been proven to alleviate this effect and attenuate HIV-1 LTR transactivation [140]. This corroborates the need to further investigate the effect of RV or analogs, not only in HIV infection but also in Tat-induced mitochondria dysfunction and ER stress in CNS. 

Piceatannol (PC), a polyphenol found in grapes and other plants such as passion fruit or sugar cane, is an RV analog [144] that is also an active SIRT1 [168]. However, the PC structure confers a higher capability to scavenge ROS by modulating other pathways as well [143]. The mechanisms of PC mitigation of ROS involve the stimulation of antioxidant enzymes such as SOD and CAT activities [144,145]. 

Moreover, PC improves mitochondrial functions by increasing complex I activity and ATP content [144]. PC has been demonstrated to induce mitochondrial biogenesis through the increase of expression and protein levels of SIRT1 and PGC1α under gamma-irradiation [144]. On the other hand, apoptosis is reduced by PC increase of anti and pro-apoptotic proteins such as Bcl-2 and BAX, respectively [145]. 

However, PC exhibits great cytoprotection potential against oxidative stressors; it was observed that at a high concentration, PC promotes depolarization of the mitochondrial membrane which leads to cell death. 

These data indicate that PC can act as an antioxidant or anticancer agent in a dose-dependent manner [143]. Polydatin, a polyphenolic compound isolated from Polygonum cuspidatum, protects against lipopolysaccharide-induced endothelial barrier disruption [169], enhances mitochondria biogenesis, increases autophagy, decreases ROS, and reduces apoptosis via activation of SIRT3 in cardiomyocytes under hypoxia [146]. 

Interestingly, in sulfur mustard-exposed L02 cells, SIRT3 expression was unchanged compared to the control. Instead, SIRT1 levels were downregulated, and polydatin treatment reversed this condition [147]. This information implies that the polydatin is a xenobiotic that can activate both SIRT1 and SIRT3 but is stressor-dependent.

6.2.2. Other Natural Compounds

Honokiol, a natural compound extracted from Magnolia species [170], activates SIRT3 by direct interaction and upregulating its gene expression in a PGC1a-dependent manner [135], which can suggest an interaction with SIRT1 since it is an activator of PGC1a, a coactivator of antioxidant enzymes [117,171]. Reports propose that honokiol also activates SIRT1 [149] and increases its gene and protein levels [148]. 

Honokiol has been implicated in ROS mitigation; increased cell viability; and decreased apoptosis [148,149] and protein levels of pro-apoptotic makers such as CHOP, p-PERK, GRP78, and CASP3 [148]. 

Among the activators of both SIRT1 and SIRT3 are dioscin, pyrroloquinoline quinone (PQQ), and melatonin. Dioscin is a saponin found in some plants that can cross the BBB [151] and exhibits neuroprotection by increasing SIRT1 and SIRT3 expression. Dioscin treatment of neurons can ameliorate ROS production, reduce cell death, and reduce neuroinflammation [138,151]. 

Indeed, it was observed that dioscin promotes autophagy by increasing Beclin-1 and LC3-II [138], to respond to cellular stressors. PQQ is a natural redox cofactor that can be found in plants. 

It has ROS scavenger potential and promotes mitochondrial biogenesis by upregulating the mRNA of NAMPT, an essential enzyme for the production of NAD+. Subsequentially, this upregulation leads to an increase in gene expression of SIRT1 and SIRT3 in HepG2 cells [152], hence increasing NAD+ availability. The following effects of PQQ are the increase of gene expression of PGC1α and downstream targets such as TFAM [152]. 

In microglia, it was proved that PQQ neuroprotective properties have been reported by activation of PINK1/parkin-mediated mitophagy in rotenone-exposed cells [172]. 

In the case of melatonin, a neurohormone produced by the pineal gland, it has been observed that SIRT3 activity rises without increasing its expression in an atherosclerosis mouse model [134] or in cadmium-exposed HepG2 cells [153]. 

This activity increase was accompanied by elevation of LC3II/I ratio, parkin expression, and decrease of mitochondrial TOM20 protein levels and acetylated FOXO3a, signifying that melatonin can induce mitophagy to protect against atherosclerosis injury through the activation of SIRT3/FOXO3a pathway [134] and activation of SOD2 [153]. 

In addition, like all the SIRT3 activators, melatonin was capable of mitigating mitochondrial ROS [134,153] and ameliorating mitochondria membrane potential loss in macrophages treated with oxidized low-density lipoprotein [134]. 

Contrary to the atherosclerosis model, Zhai et al. [133] found that melatonin increased both the expression and activity of SIRT3 in myocardial ischemia/reperfusion injury. Interestingly, melatonin also increases protein levels of SIRT1 [133,154], and the same group observed that when SIRT1 was inhibited or silent, SIRT3 expression was affected but not in the other direction [133]. 

Lipopolysaccharide-induced oxidative stress in microglia causes a decrease in nuclear Nrf2 and its downstream genes, which is reversed by melatonin SIRT1 interaction [154]. Furthermore, it was reported that melatonin reduces ER stress in the cortex of the brain under cerebral hypoxia-ischemia through the reduction of activation of PERK and ATF-6 UPR pathways and the increase in SIRT1 levels [155]. 

The translocation of SIRT1 to the cytoplasm is related to apoptosis, an observation made in CoCl2-exposed microglia and blocked by melatonin treatment [156]. In agreement with this information, melatonin-mediated SIRT1 activation and nuclear translocation are also related to mitochondrial biogenesis via the increase of PGC1α [157]. 

Accordingly, the SIRT1 pathway is intimately related to SIRT3 in the amelioration of stressor-induced mitophagy and therefore must be considered to further investigate both regulations in Tat-exposed neural cells. 

Another natural xenobiotic is dihydromyricetin (DH), a flavonoid present in plants such as Ampelopsis grossedentata, which has been found to confer protection in liver injury and cardiovascular, dermatological, and neurodegenerative diseases [173]. DH increases SIRT3 protein levels via PGC1α and induces mitophagy in murine chondrocytes [158]. 

SIRT3 can also be modulated by silybin, an extract from Silybum marianum. Silybin induces the reduction of ROS; apoptosis; and mitochondria dysfunction, and increases energy metabolism in cells exposed to cisplatin, an anticancer drug that causes acute kidney injury [160]. 

Additionally, SIRT3 modulates ROS by deacetylation of MnSOD, which is increased by treatment with phloretin, a molecule found in apples and pears [174]. Oxidative modulation can be activated by β-apache (LP), a quinone compound extracted from Tabebuia avellanedae, which has several beneficial effects, from anticancer to neuroprotective properties. For instance, in a murine of Huntington's disease, LP increases SIRT1 protein and thus deacetylation of PGC1α and decreases mitochondrial superoxide, meaning that LP can promote mitochondrial biogenesis and ROS amelioration [159]. 

Finally, Tanshinone IIA (TAN), a compound extracted from Salvia miltiorrhiza, has been reported to have neuroprotective properties. TAN can activate the LKB1-AMPK pathway by increasing SRT1 activity in mouse bone marrow-derived mast cells [164]. 

Moreover, TAN can restore mitochondrial function by preventing mPTP opening and thus intrinsic apoptotic pathway activation in microvascular endothelial cells exposed to a stressor [165]. In line with these data, TAN can reduce Tat-induced cytotoxicity in TZM-bl cells via Nampt activation, which in turn increases NAD+ availability, which subsequently activates SIRT1. 

This activation cascade is responsible for ROS decrease and inhibition of HIV transactivation [166]. Remarkably, this study provides evidence supporting the role of SIRTs activation in the mitigation of Tat effects on cells.

6.2.3. Synthetic Drugs

Due to the lack of specificity of some natural xenobiotics, synthetic drugs have been developed to increase SIRT activity, including SRT2104 [175] and SRT1720 [163]. SRT2014 can penetrate the BBB effectively, and it has been involved in neuroprotection by upregulating autophagy [162,175]. SRT1720 has been reported to upregulate key proteins of mitochondrial biogenesis PGC1α and bioenergetic-related proteins such as ATP synthetase c [163]. Metformin, a drug used in type 2 diabetes, can increase SIRT3 expression in peripheral blood leukocytes of type 2 diabetes patients and low mitochondria ROS [161].

6.2.4. NAD+ as Co-Substrate of SIRTs

There is great interest in exogenous SIRTs activator compounds; however, other endogenous modulator molecules can be used as SIRTs activators such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are precursors of nicotinamide adenine dinucleotide (NAD+). This coenzyme is essential for SIRT deacetylation activity. Interestingly, even though SIRT1 mRNA levels increase with age in animal brains, there is a deterioration in its enzymatic activity, which is related to the NAD+ decline [84]. 

Notably, not all SIRTs are NAD-dependent in the same manner since SIRT1 and SIRT3 have higher Km values than the other SIRTs, meaning that their function is favorable when NAD+ levels are higher [176]; therefore, increasing NAD+ concentration may restore their enzymatic activity. NAD+ syntheses from NMN or NR are different because the first requires a one-step reaction while the other involves a phosphorylation step to be transformed into NMN and then NAD+, mediated by NMN/NAMN adenylyltransferase (NMNAT). 

These reactions occur in the cytoplasm, but recent evidence has shown the mitochondrial uptake of NR and NMN, which is supported by the localization of NMNAT in this organelle as well [176]. NMN has been reported to increase NAD+ concentration [137] and improve cognition by inhibiting the JNK pathway, synapse loss, and neuroinflammation in a murine model of AD [177]. 

Additionally, in the presence of a mitochondrial complex I inhibitor, NMN rescues mitochondrial ATP production and prevents apoptosis [137]. Conversely, NR supplementation also can increase NAD+ levels in brain NR and has been evaluated in AD models, resulting in attenuation of cognitive impairment in vivo by increasing levels of PGC1a, which in turn is associated with the prevention of amyloid-β production [178], suggesting that SIRT1-mediated activation of PGC1a must be involved. 

HIV has been reported to decrease cellular NAD+ levels [179]. Zhang et al. [140] found a reduction of NAD+ levels in cells exposed to Tat [140], which is related to SIRTs' enzymatic activity. Furthermore, Tat-induced NAD+ depletion is mediated by miT-182 via the down-regulation of NAMPT, which is the enzyme needed for the conversion of nicotinamide (NAM) to NMN [180].

7. Conclusions and Future Directions

Nowadays, PLWH can have a longer life expectancy thanks to cART. However, neuronal alterations are emerging that eventually will lead to HAND. Even though the milder forms are the most persistent in this population, it is necessary to find the molecular mechanisms governing neurodegeneration. Meanwhile, cART controls HIV pathogenesis, and there is evidence regarding its cytotoxicity effects. Additionally, infected cells that cross the BBB produce and secrete viral proteins that present neurotoxicity properties. 

Tat, a transactivator of HIV transcription, has a significant capacity to internalize into neurons causing neurotoxicity through several mechanisms such as ER stress and mitochondria dysfunction, which provoke cell death. Tat induces inhibition of SIRT1 and SIRT3 activities, meaning that Tat-mediated dysregulation of any of these molecules contributes to the neuropathogenesis of HAND; hence, these SIRTs are part of regulatory pathways that influence cell survival. Tat-induced neurotoxicity impairs these vias, so modulation of SIRTs is a promising therapy against neurodegeneration. 

Furthermore, studies have been conducted to test the available xenobiotics that regain the deacetylation activity of SIRTs in the context of neurodegenerative diseases and have obtained favorable results. It is known that SIRT activators work by using different strategies; on the one hand, the exogenous modulators such as resveratrol activate SIRT1/SIRT3, while endogenous modulators such as NR increase NAD+ concentrations. In addition, it was reported that from the seven SIRTs, not only SIRT1 and SIRT3 could interact directly with Tat but also SIRT2. 

The effect of this interaction remains unclear even though SIRT2 also participates in the evolution of neurodegenerative diseases. In consequence, more studies are needed to elude inhibition/activation actions of all SIRTs in Tat-mediated neurotoxicity conditions so they can be taken collectively to generate the desired outcomes in the CNS after their modulation. Finally, despite cART being essential to maintaining a low viral load, it cannot prevent the development of HAND, so adjuvant treatment is required. 

This additional therapy must be centered on regulators of hallmark-altered pathways of neurodegeneration. Due to the current lack of specific medication for HAND and given that sirtuins are by no means pivotal enzymes in Tat-induced neurotoxicity, focusing on their modulation must be part of a therapeutic strategy to prevent and mitigate HAND.

Author Contributions: Conceptualization, I.F.-C. and M.E.-D.; investigation, I.F.-C. and J.E.G.-S.; writing-original draft preparation, I.F.-C.; writing-review and editing, B.M.T.-M., G.V.G.-E. and E.V.-V. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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