SIRT3 is a mitochondrial NAD⁺-dependent deacetylase that plays critical roles in cellular energy metabolism, oxidative stress response, and apoptosis regulation (Shen et al., 2020). The gene of SIRT3 is located on human chromosome 11p15.5, encoding a 399-amino acid protein with a full-length molecular weight of approximately 44 kDa. Upon mitochondrial translocation, the mitochondrial targeting sequence (MTS) is cleaved, yielding mature SIRT3 with a molecular weight of about 28 kDa (Lescai et al., 2009; Donadini et al., 2013). The protein structure comprises a large domain and a small domain connected by a flexible loop region, forming a stable catalytic core. The large domain contains a Rossmann fold responsible for NAD⁺ binding and providing fundamental structural elements for catalytic activity, while the small domain stabilizes NAD⁺ binding and regulates substrate access to the catalytic pocket (Zhang J. et al., 2020). Additionally, the C-terminal region mediates protein-protein interactions to enhance substrate specificity or modulate enzymatic activity (Jin et al., 2009a). The intricate structural architecture of SIRT3 underpins its multifunctional roles.

SIRT3 primarily localizes to the mitochondrial matrix, and its sub-cell localization is tightly regulated by the MTS, transmembrane transport systems, post-translational modifications (PTMs), and intracellular signaling pathways (Zhang et al., 2015). The mRNA of SIRT3 is translated by free ribosomes in the cytoplasm, producing a precursor protein containing the MTS. This sequence, approximately 30 amino acids in length and enriched in arginine and lysine, confers mitochondrial affinity (Bao et al., 2010; Jin et al., 2009a). Besides, it can be recognized by the translocase of the outer mitochondrial membrane and translocase of the inner mitochondrial membrane complexes, mediating the transmembrane transport of SIRT3 (Zhang J. et al., 2020). Upon entering the mitochondrial matrix, the MTS of SIRT3 is cleaved by mitochondrial processing peptidase (MPP) at residues Arg31 and Ala32, forming a mature protein with intact catalytic activity (Ansari et al., 2017). The mature SIRT3 predominantly anchors to mitochondrial matrix protein complexes and stabilizes through interactions with mitochondrial matrix proteins such as heat shock protein 60 and heat shock protein 70 (Yang et al., 2011; Hu et al., 2022) (Figure 2b).

SIRT3 exhibited higher catalytic efficiency compared to Sirtuin-1 (SIRT1) and Sirtuin-2 (SIRT2). Firstly, mitochondria serve as the central hub for cellular energy metabolism and oxidative stress responses. Meanwhile, due to the hydrophobic pocket within the catalytic domain of SIRT3, SIRT3 can recognize complex groups (Zhang et al., 2019) (Figure 1), thereby enabling it to react with more substrates. Secondly, the catalytic activity of SIRT3 relies on NAD+ and involves multiple key amino acid residues, with His-248 serving as the core catalytic residue (Jin et al., 2009b). SIRT3 participates in physiological or pathological processes by mediating the deacetylation of diverse biological macromolecules (Lambona et al., 2024). Studies demonstrated that the enzymatic activity of SIRT3 is directly regulated by NAD + concentration and increasing proportionally with elevated NAD+/NADH ratios (Lambona et al., 2024; Feldman et al., 2015; Anderson et al., 2017).

The expressions of SIRT3 are regulated at multiple levels, including gene transcription, mRNA stability, PTMs, protein stability, and enzymatic activity. These mechanisms work synergistically under diverse physiological and pathological conditions to maintain mitochondrial metabolic homeostasis and cellular energy balance. For example, the promoter region of the SIRT3 gene contains multiple transcription factor binding sites. It is positively regulated by nuclear factor erythroid 2-related factor 2 (Nrf2), while hypoxia-inducible factor 1alpha (HIF-1α) suppress its transcription under hypoxic or stress conditions (Loboda et al., 2009; Yao et al., 2022) (Figure 2a). Metabolic regulatory signals also influence the transcriptional level of SIRT3. Chronic exposure to biochemical stress or mitochondrial metabolic abnormalities can accumulate ROS intracellularly, generating excessive superoxide, hydrogen peroxide, and hydroxyl radicals (Albano, 2006). These sequentially activate the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and PGC-1α, thereby enhancing SIRT3 transcription (Wang Y. et al., 2025; Wang et al., 2022). On the other hand, nuclear-localized SIRT1 also participates in the positive regulation of SIRT3 expression by deacetylating PGC-1α in the nucleus (Zhang et al., 2021; Rodgers et al., 2005) (Figure 2d).

SIRT3 modulates energy metabolism, antioxidant responses, and mitochondrial homeostasis by deacetylating specific sites on key metabolic enzymes (Table 1). SIRT3 enhances the activity of long-chain acyl CoA dehydrogenase (LCAD) through deacetylation, accelerating fatty acid β-oxidation and promoting the generation of more acetyl-CoA. Via the tricarboxylic acid cycle, this process boosts ATP production (Hirschey et al., 2010). For glutamatergic neurons, this step helps enhance synaptic transmission efficiency. On the other hand, deacetylation of ATP synthase β by SIRT3 strengthens its catalytic activity, improving the ATP synthesis efficiency at the terminal of the mitochondrial electron transport chain and increasing the availability of ATP in the cytoplasm to maintain synaptic vesicle cycling and neuronal electrical activity (Zhang et al., 2016). The increased ATP production also activates the protein kinase A/cAMP-response element binding protein (PKA/CREB) pathway, leading to CREB phosphorylation and promoting the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which can enhance neuronal survival and plasticity (Mo et al., 2024) (Figure 2c).

As previously mentioned, elevated ROS in the cytoplasm can increase SIRT3 expression by activating the AMPK/PGC-1α pathway. In turn, SIRT3 deacetylates SOD2 and isocitrate dehydrogenase 2 (IDH2), significantly enhancing their enzymatic activity to inhibit ROS (Dikalova et al., 2017; Zou et al., 2017). On the other hand, SIRT3-mediated deacetylation of forkhead box O3 (FoxO3a) in mitochondria activates FoxO3a-dependent gene expression (Jacobs et al., 2008). This not only regulates SOD2 to inhibit ROS but also enhances the activity of catalase, achieving clearance of hydrogen peroxide and reducing oxidative stress. Overall, SIRT3 plays a critical role in maintaining intracellular ROS homeostasis (Figure 2d).

Optic atrophy 1 (OPA1) is a critical regulatory protein involved in maintaining mitochondrial inner membrane fusion and the formation of mitochondrial cristae structures (von der Malsburg et al., 2023). The regulation of OPA1 by SIRT3 facilitates the repair and functional recovery of mitochondrial structures, preventing mitochondrial fragmentation (Chen et al., 2024b; Samant et al., 2014). The opening of the mitochondrial permeability transition pore (mPTP) is a hallmark of mitochondrial dysfunction, which is closely associated with excessive acetylation of cyclophilin D (CypD) (Dikalova et al., 2024). By deacetylating CypD, SIRT3 modulates mPTP activity to inhibit the release of cytochrome C, which suppresses the activation of Caspase-3 and ultimately inhibiting apoptosis (Yan et al., 2022; Poppe et al., 2001) (Figure 2e).

Glutamate is the main excitatory neurotransmitter in the vertebrate brain. Its excessive release triggers membrane depolarization through receptor-mediated Na⁺ and Ca²⁺ influx, increasing neuronal mitochondrial oxidative phosphorylation and superoxide production (Rueda et al., 2016). A study on cortical mitochondria of SIRT3 knockout (KO) mice showed that the lack of SIRT3 affected the subcellular regulation of Ca²⁺ after glutamate induced Ca²⁺ influx and confirmed through neuronal cell and mouse running experiments that glutamatergic signaling mediates the upregulation of SIRT3. The bidirectional regulatory effect between SIRT3 and glutamatergic neurons enhanced the resistance to degeneration in hippocampal and cortical neurons (Cheng et al., 2016). The reduced incorporation of [1,6–13C]glucose-derived carbon into all isotopomers of glutamate, glutamine, γ-aminobutyric acid (GABA), and aspartate in SIRT3 knockout brains demonstrated diminished mitochondrial metabolic activity and tricarboxylic acid cycle flux in both neuronal and astrocytic compartments (Kristian et al., 2021). Continuous high levels of Ca²⁺ activated protein phosphatase 4, leading to high doses of glutamate inhibiting the AMPK/PGC-1α/SIRT3 pathway, while brief increased in Ca²⁺ levels could activate this pathway, providing important insights for precise regulation of glutamate and SIRT3 levels to alleviate brain related diseases (Gu et al., 2023). There are gender differences between glutamate and SIRT3. It was reported that the lack of SIRT3 significantly increased the expression of N-methyl-D-aspartate (NMDA) receptor in the hippocampus of female SIRT3 KO mice only. Excessive upregulation of NMDA receptor 2B could enhance glutamatergic excitotoxicity, affecting primary neural development and synaptic plasticity (Allen et al., 2023). Based on the complex relationship between glutamate and SIRT3, further exploration of strategies to balance their expression may provide novel therapeutic directions for neurological diseases.

GABA is an inhibitory neurotransmitter that has effects on learning, sleep, memory, and muscle movement. Dysfunction and degeneration of GABAergic neurons lead to abnormal hyperexcitability of neural circuits, also causing degeneration of glutamatergic neurons (Palop and Mucke, 2016). After treatment with diazepam, the activation of GABA receptors significantly reduced seizures induced by kainic acid in SIRT3^+/− AppPs1 mice. The experiment also showed that the loss of GABAergic neurons and the exacerbation of neural network overexcitation were caused by a decrease in SIRT3 (Cheng et al., 2020). Intermittent fasting improves multiple health indicators and can slow down the progression of diabetes, vascular disorders, and AD (Mattson et al., 2018). Experiment on SIRT3 KO mice demonstrated that SIRT3 was essential for enhancing GABAergic synaptic transmission adaptability and counteracted anxiety during intermittent fasting (Liu et al., 2019). In rats with middle cerebral artery occlusion, the neuroprotective effects of wogonoside in cerebral ischemia-reperfusion injury were mediated through regulating GABAergic amino acid metabolism, mitochondrial bioenergetics, and glutathione biosynthesis pathways, which collectively preserved redox equilibrium while suppressing oxidative damage through attenuation of reactive oxygen species overproduction (Xu et al., 2024). In summary, GABAergic neurons not only ameliorate neurological disorders through interactions with SIRT3 but also exhibit complex interplay with glutamatergic neurons.

Midbrain dopaminergic neurons have been a focal point of intensive research. The nigrostriatal dopamine system is crucial for coordinating fine motor skills and maintaining movement balance. The degeneration of dopaminergic neurons in the substantia nigra is an important pathological mechanism of Parkinson’s disease (PD) (Arenas et al., 2015). It was reported that SIRT3 KO mice exhibited significantly elevated acetylation levels of manganese superoxide dismutase (MnSOD) on lysine 68 in substantia nigra pars compacta dopaminergic neurons compared to wild-type (WT) mice, alongside its mitochondrial MnSOD activity was significantly lower than that of WT mice. This proves that in mouse substantia nigra pars compacta dopaminergic neurons, SIRT3 deacetylates MnSOD on lysine 68 to increase its activity and reduce mitochondrial oxidative stress (Shi et al., 2017). In vitro experiments using MN9D cells revealed that SIRT3 promoted mitochondrial autophagy while inhibiting activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in dopaminergic neurons (Jiang et al., 2022). Additionally, SIRT3 also mitigated oxidative stress-induced neurotoxicity in dopaminergic neurons (Lee et al., 2021). For instance, SIRT3 directly deacetylated SOD2 and adenosine triphosphate (ATP) synthase β in dopaminergic neurons to prevent cell death (Zhang et al., 2016). In the rat model of subarachnoid hemorrhage, dopamine-D2-agonists were shown to inhibit mitochondrial fission mediated by dynamin-related protein 1, via activating mitofusin 2 and optic atrophy 1. On the other hand, dopamine-D2-agonists regulated PGC-1α/SIRT3 pathway by restricting cytochrome C in mitochondria, which could improve mitochondrial dysfunction and exert neuroprotective effects (Rehman et al., 2025). To summarize, these findings highlighted the bidirectional regulatory interactions between SIRT3 and dopaminergic neurons, which collectively maintain neuronal homeostasis.

Astrocytes are widely distributed in the mammalian brain, and involve in maintaining the neurovascular unit, facilitating synaptic network formation, regulating ionic balance, regulating synaptic neurotransmitter concentrations, and synthesizing bioactive molecules that influence neuronal activity (Khakh and Deneen, 2019). Cell experiments showed that hyperglycemic conditions significantly enhanced the susceptibility of SIRT3 to recurrent low glucose, inducing mitochondrial structural abnormalities in astrocytes. However, overexpression of SIRT3 demonstrated preservation of mitochondrial bioenergetics while decreasing oxidative damage biomarkers induced by recurrent low glucose. Meanwhile, SIRT3 inhibited the transformation of astrocytes into neuroinflammatory A1 like reactive phenotype (Gao R. et al., 2022). It was also reported that SIRT3 could modify astrocyte activation by regulating the Notch1/NF-κB pathway, alleviating inflammatory responses following status epilepticus (Zhu et al., 2024). As for ischemic stroke, SIRT3 exerted a protective effect by regulating the HIF-1α/VEGF pathway in astrocytes (Yang X. et al., 2021). Furthermore, SIRT3 prevents astrocyte A1 polarization and associated neurotoxicity under chronic hypoxia by inhibiting phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription 3 (STAT3) (Hu et al., 2023). Research indicated that caffeine improved astrocyte-mediated protein Tau (Tau) neurotoxicity via modulation of the EGR1/SIRT3 pathway (Gao et al., 2024). In total, the roles of SIRT3 in astrocytes are complex and critical, demonstrating its potential to mitigate astrocyte injury and protect CNS targets.

Astrocytes, oligodendrocytes, and microglia are the main glial cells in CNS. The main functions of oligodendrocytes include wrapping around axons, forming myelin sheaths, assisting in the efficient transmission of biological electrical signals, and maintaining the normal function of neurons (Emery and Wood, 2024). Microglia, characterized by their multipolar morphology and plasticity, are immune effector cells in CNS and play critical roles in physiological processes (Colonna and Butovsky, 2017). Studies demonstrated enhanced expression of SIRT3 in astrocytes, oligodendrocytes, and microglia within the white matter of hypoxic newborn rats. Meanwhile, early hypoxia induced intense SIRT3 expression in microglia (Li X. et al., 2018). Quantitative PCR analyses across neuron subtypes revealed that SIRT3 exhibits the highest expression in primary neurons, followed by astrocytes, while oligodendrocytes and microglia show the lowest levels. PGC-1α altered the expression level of SIRT3 in neurons. Among different types of cells in PGC-1α KO mice, the expression level of SIRT3 was highest in astrocytes but lower than in WT mice (Buck et al., 2017).

Ischemic stroke is primarily caused by cerebral blood flow interruption due to large-vessel atherosclerosis, small-vessel lacunar infarction, or cardioembolism (Sommer, 2017), which makes the brain starve of oxygen and glucose, leading to neuronal energy metabolism failure and secondary cell damage (Qin et al., 2022). Recent studies demonstrated that SIRT3 could repair mitochondrial ultrastructure and membrane composition, promote mitochondrial biogenesis, and alleviate mitochondrial dysfunction by upregulating the expression and activity of optic atrophy 1 (Chen et al., 2024b). Besides, SIRT3 also inhibited the expression of voltage-dependent anion channel 1 and adenine nucleotide translocase 1, preventing abnormal opening of the mitochondrial permeability transition pore and reducing mitochondrial apoptosis during ischemic injury (Yang Y. et al., 2021). Metabolomic analysis showed a significant increase in GABA and glutathione levels in the brain after wogonoside treatment, confirming that SIRT3 not only had ability to mitigate oxidative stress but also alleviated excitotoxicity caused by excessive glutamate release (Xu et al., 2024). Also, SIRT3 protects the integrity of the blood-brain barrier (BBB) in ischemic stroke mice by regulating the HIF-1α/VEGF pathway in astrocytes, reducing inflammatory responses and neuronal apoptosis (Yang X. et al., 2021). SIRT3 can also promote the migration of microglia in ischemic stroke by increasing the expression of CX3C chemokine receptor 1 (Cao et al., 2019). Furthermore, SIRT3 promoted PINK1/Parkin mediated mitochondrial autophagy, increased microvascular density and the expression of VEGF A, and reduced neuronal apoptosis in cerebral ischemia-reperfusion model rats (Wei et al., 2023). On the other hand, overexpression of SIRT1 can improve mitochondrial respiratory chain dysfunction by enhancing the deacetylation activity of SIRT3, reflecting the synergistic effect of the two in restoring mitochondrial structure and function (Chen et al., 2024c). However, the direct molecular interaction between SIRT1 and SIRT3 is not yet clear, and the synergistic effect lacks causal validation through gene knockout or dual intervention experiments. In general, intervention studies validated the therapeutic potential of SIRT3 for ischemic stroke (Table 2), but it is still necessary to explore its targeting ability and provide new directions for clinical treatment.

Diabetic cerebral ischemia-reperfusion injury (CIRI) refers to the secondary brain tissue damage caused by the restoration of cerebral blood flow after ischemic interruption in diabetic patients, leading to more severe neurological dysfunction (Zhou et al., 2025). Its main pathological mechanisms include enhanced inflammatory responses, exacerbated oxidative stress, and mitochondrial dysfunction (Przykaza, 2021). It was found that in diabetic CIRI rats, the levels of SIRT1/SIRT3 are significantly reduced, accompanied by decreased levels of mitochondria-regenerating proteins such as PGC-1α, nuclear respiratory factor 1 (NRF1), and transcription factor A (TFAM). This suggests that diabetes may hinder mitochondrial regeneration by inhibiting the SIRT1/SIRT3-PGC-1α-NRF1-TFAM signaling pathway, thereby exacerbating cerebral ischemia-reperfusion injury in rats (Xin et al., 2025). Although research on this topic is limited, existing data still confirms the critical protective role of SIRT3 in CIRI. For example, melatonin can alleviate CIRI in diabetic mice by activating the protein kinase B (Akt)/SIRT3/SOD2 pathway and improving mitochondrial damage. However, when SIRT3 upregulation is suppressed by 3-TYP, these protective effects are attenuated, confirming that SIRT3 plays a key role in diabetic cerebral ischemia-reperfusion injury (Liu L. et al., 2021). Further studies have demonstrated that rapamycin can maintain mitochondrial dynamic balance by regulating the SIRT3-dynamin-related protein 1 (DRP1)/OPA1 signaling pathway, thereby improving CIRI in diabetic rats (Hei et al., 2023). Given all that, exploring the synergistic interactions of SIRT3 and its differential expression in various neuron types will provide strong support for precise treatment of CIRI. Additionally, as a comorbidity of diabetes, clarifying the mechanism of SIRT3 in diabetes is of great significance for halting the further progression of neurological damage.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting spinal α-motor neurons, characterized by muscle atrophy, loss of movement function, and respiratory failure. Pathological mechanisms of ALS include mitochondrial dysfunction, ROS accumulation, and protein misfolding (Suk and Rousseaux, 2020). The decrease in SIRT3 expression affected mitochondrial electron transport chain function in anterior horn motor neurons of ALS patients. This leads to insufficient energy supply to neurons, exacerbating oxidative stress damage (Hor et al., 2021). Low SIRT3 expression reduced neuronal tolerance to metabolic stress and accelerated neuronal death and muscle atrophy though AMPK/PGC-1α axis (Kuczynska et al., 2021). SIRT3 KO ALS mice showed decreased muscle strength, decreased survival rate of motor neurons, significant axonal atrophy, and myelin sheath degeneration, while the overexpression of SIRT3 attenuated neuronal damage and delayed muscle atrophy progression (Buck et al., 2017). Additionally, NAM could improve movement function and antioxidant capacity in ALS animal models (Hor et al., 2021). It was also shown that NAD⁺ precursors enhance mitochondrial bioenergetics in ALS patients and improve muscle control and movement function (Obrador et al., 2021). Although previous studies suggested that the activation of SIRT3 could reverse metabolic defects in motor neurons and alleviate symptoms, no clinical trials targeting SIRT3 were conducted in human patients to date. Future studies should advance clinical trials to explore SIRT3-targeted therapies in ALS patients.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. The neuropathology comprises inflammatory demyelination, axonal transection, and progressive neurodegeneration. Clinically, it manifests as movement disorders, sensory disturbances, visual impairment, and progressive cognitive decline (Woo et al., 2024). It was found that SIRT3 plays a critical role in maintaining energy metabolism and antioxidant defense in oligodendrocytes. Low SIRT3 expression decreased the activity of electron transport chain, promoted ROS accumulation, exacerbated neuroinflammation, and impaired remyelination capacity (Singh et al., 2018; Khodaei et al., 2019). For MS mice treated with ellagic acid, both myelin regeneration ability and movement function were improved, suggesting that SIRT3 may slow down MS progression by enhancing mitochondrial function and antioxidant capacity (Khodaei et al., 2019). Furthermore, SIRT3 regulated myelin homeostasis via the Nrf2-mediated antioxidant pathway. For MS patients, decreased expression of SIRT3 could impair myelin regeneration ability, weaken axonal protection mechanisms, and lead to disease progression (Theodosis-Nobelos and Rekka, 2022). As a potential therapeutic target for MS, intervention in its regulation strategy is expected to provide new treatment ideas for MS patients. This is beneficial for improving remyelination, slowing down disease progression, and improving patients’ quality of life.

Epilepsy, a chronic brain disorder, arises from excessive synchronous neuronal activity in the central nervous system, accompanied by mitochondrial impairment, disrupted neurotransmitter homeostasis, and inflammatory cascades as core pathophysiological hallmarks (Milligan, 2021). A prospective observational study reported that SIRT3 levels were significantly decreased in epilepsy patients, and even lower in drug-resistant epilepsy cases (Hu et al., 2024). Research showed that blocking MciroRNA-134–5p activity preserved neuronal integrity against kainic acid neurotoxicity via SIRT3-dependent mechanisms that maintain mitochondrial homeostasis (Lin et al., 2021). Additionally, SIRT3 regulated astrocyte activation via the Notch1/NF-κB pathway, which helps alleviate the inflammatory response after epilepsy (Zhu et al., 2024). And the regulation of the NLRP3/BDNF/SIRT3 axis could reduce inflammation and oxidative stress during seizures, improving cognitive impairment caused by seizure (Fawzy et al., 2025). On the other hand, citric acid treatment in epileptic rats increased SIRT3 expression, which promoted mitochondrial autophagy and reduced hippocampal oxidative stress and apoptosis (Wu et al., 2020). It is worth noting that SIRT3 could enhance autophagy by regulating the AMPK/mTOR pathway to exert a protective effect against epilepsy induced brain damage (Chen et al. 2024a). The probability of epilepsy in patients with diabetes is significantly higher than that in normal people. Insulin could activate the SIRT1/PGC-1α/SIRT3 pathway, prolonging seizure latency, reducing seizure severity, reversing mitochondrial dysfunction, and lowering oxidative stress levels (Cheng et al., 2021). The discovery of anticonvulsant effects mediated by insulin revealed innovative strategies for health management in diabetic populations (Chou et al., 2016).