Natural products contain a wide range of biologically active metabolites (Park et al., 2021). These compounds usually originate from complex biosynthetic systems and exhibit various morphological characteristics (Nair and Jez, 2020). They can be used in pharmaceutical research and development and drug design, as well as in dietary supplements, natural foods without artificial ingredients, and cosmetics (Newman and Cragg, 2012; Nair and Jez, 2020; Park et al., 2021). In this study, we focused on botanical drugs derived from natural products. Natural products are characterized by their chemical diversity and complexity. Many metabolites contain a large number of stereo-specific carbon centers. Thus, an increasing number of scientists are interested in the stereo-complexity of these molecules (Katz and Baltz, 2016). With the continuous development of natural product research, which began with the discovery and medical application of antibiotics in the 1950s, the average lifetime of the population increased significantly over the following 10–15 years (Bérdy, 2012). Katz and Baltz divided the history of natural product discovery into three overlapping periods, from the 1940s–1970s, 1970s–2000s, and beyond 2000 according to their impact on the discovery of new natural products. The first 30 years, the phenotypic screening stage, mainly focused on the discovery of antibacterial and antifungal metabolites; the second 30 years encompassed a huge expansion of screening methods and strategies; the third 30 years incorporated genomics-based approaches (Katz and Baltz, 2016). With the rapid development of science and technology, machine learning models have been used to predict the biochemical and physiological effects of natural products (Jeon et al., 2021). Hence, machine learning models are expected to have a significant impact on the future development and research of the molecular structures of natural products.

Mitochondria are multifunctional organelles (Nunnari and Suomalainen, 2012; Chandel, 2014) that have multiple functions, from bioenergy to cell signaling, and are signaling centers that induce transcription, proteomic, and posttranslational regulation mechanisms (Khacho and Slack, 2017). Mitochondrial function and mitochondrial dynamics play important roles in the process of neural development. Mitochondria play a central role in determining the fate of neural stem cells (NSCs) (Khacho et al., 2019). In the central nervous system, mitochondrial diseases are characterized by cognitive dysfunction, which leads to behavioral abnormalities (Fattal et al., 2006). Metabolic disorders caused by mutations in mitochondrial or nuclear DNA often affect many organs and systems. Among them, nervous system symptoms are the most common and most serious (McFarland et al., 2010), and they manifest as epilepsy, cognitive dysfunction, progressive dementia, and lactic acidosis (Kartsounis et al., 1992; Turconi et al., 1999). Mitochondria maintain their total number and morphology mainly through the regulation of the counterbalance between fission and fusion, namely mitochondrial dynamics. Therefore, changes in mitochondrial morphology and function are indispensable in the process of neurogenesis.

The mitochondria facilitate adenosine triphosphate (ATP) production, calcium regulation, and redox maintenance, hence their dysfunction can lead to various neurodegenerative diseases, including Alzheimer’s disease (AD) (Xia et al., 2018). Mitochondrial and synaptic dysfunction has been proven to be an early symptom of AD (Pérez et al., 2018). To date, there is no standard treatment for mitochondrial disorders. With the development of medical treatments, multiple pharmacological properties of botanical drugs have been applied to study neurodegenerative diseases, such as salidroside and astragalus polysaccharides, which have a protective effect on cognitive-related changes (Zhang et al., 2019; Xie et al., 2020). Asiatic acid can prevent and alleviate seizures (Lu et al., 2021).

Currently, an increasing number of natural product extracts involved in mitochondrial regulation have attracted attention, including their effects on mitochondrial dynamics and autophagy. Therefore, this study reviews the literature on natural products’ regulation of mitochondrial function in cognitive dysfunction diseases to clarify the possible mechanism underlying mitochondrial function as influenced by natural products, identify new therapeutic targets for the treatment of neurodegenerative diseases, and provide an insight into the development of natural products for the treatment of cognitive impairment.

In the present study, 408 articles were initially retrieved from the database. An additional article related to the purpose of the present study was found through a manual search. A total of 108 repetitive articles were excluded (96 duplicate articles automatically removed by EndNote software, and 12 articles were excluded manually), 274 articles were excluded through article titles and abstract screening, and 13 articles were dropped after full-text screening as they did not meet the purpose of this study. Fourteen articles were included in the final analysis (Figure 1).

Mitochondria are multifunctional organelles with an independent genome, and mutations to their genes and structural damage are key factors underlying cognitive impairment in neurodegenerative diseases (Khacho et al., 2019) (Figure 2). Neurons are highly dependent on mitochondria; 20% of the body’s oxygen is consumed by ATP produced by mitochondrial respiration in the brain (Attwell and Laughlin, 2001). Furthermore, the brain consumes 20% of the body’s total glucose intake, especially the nerve cells (Sokoloff, 1999). Although glycolysis can provide some ATP, most ATP is produced by mitochondrial respiration (Rangaraju et al., 2014). Mitochondria play an important role in the maintenance of physiological functions (Misgeld and Schwarz, 2017). Through continuous fission and fusion, a network structure with inner and outer membranes and multiple nucleoli containing mitochondrial DNA is formed (Braschi and McBride, 2010; Nabi et al., 2022). However, errors in mitochondrial fission or fusion can lead to nervous system diseases of varying degrees, and cognitive dysfunction is one of them. Pérez et al. (2018) reported that mitochondrial dysfunction is mediated by abnormal microtubule-associated proteins.

At present, the pathogenesis of neurodegenerative diseases, such as AD, remains incomplete. Many recent studies have discussed the relationship between mitochondrial dysfunction and AD (Klein et al., 2021; Takeda et al., 2021). Tau is a key protein involved in the pathogenesis of AD. Pérez et al. (2018) showed that Tau pathology impaired mitochondrial transport affected mitochondrial dynamics and bioenergetics in AD. Multiple studies have shown that mitochondrial dysfunction is an early symptom of AD (Gibson and Shi, 2010; Cabezas-Opazo et al., 2015) and a driving factor of cognitive impairment in AD. Since mitochondria are easily affected by age, mutations, and metal toxins, dysfunction caused by mitochondrial DNA (mtDNA) damage, mutation, and impairment of metabolism and protein transport may lead to accumulation of Aβ oligomers or fibrils and phosphorylated Tau. Furthermore, the accumulation of damaged mtDNA and other macromolecules during aging leads to metabolic disorders (Abyadeh et al., 2021). The accumulation of damaged mitochondria further accelerates the progression of cognitive dysfunction (Swerdlow, 2018). The dysfunction of mitochondria further leads to the lack of bioenergy, the imbalance of intracellular calcium regulation, and the generation of free radicals. This causes oxidative stress and consequently to aggravation of Aβ oligomeric and Tau pathology, which, in turn, aggravates further synaptic dysfunction, mitochondrial damage, memory loss, and cognitive impairment (Figure 3).

Multiple studies have identified mitochondrial dysfunction as the central mechanism underlying many neurodegenerative diseases (Macdonald et al., 2018; Sharma et al., 2021). Significant progress has been made in understanding mitochondrial diseases, and there are now many treatments available for neurodegenerative diseases, including antioxidants, mitochondrial inducers, energy buffers, and gene therapy. However, satisfactory treatments are still lacking. Natural products have been used in various fields since the emergence of early antibiotics. Penicillin from mold, morphine from poppy, and paclitaxel, an anti-cancer drug, are typical examples of natural product drugs (Hunter, 2008). Natural product preparations may be an important breakthrough in the treatment of neurodegenerative diseases. Most natural products are extracted from microorganisms and exhibit a certain degree of cytotoxicity (Hunter, 2008). Therefore, when used clinically, they should be scientifically verified through clinical drug research at different levels.

The natural products discussed here mainly refer to the natural ingredients extracted from botanical drugs. An et al. (2021) reported that when DZXI (extracted from botanical drugs (Chai et al., 2013)) was administered to patients with acute ischemic stroke (AIS), the neurological and cognitive impairment of these patients was improved by regulating the mitochondrial respiratory chain and retaining the mitochondrial structure in brain tissue. Clinical studies have shown that DZXI treatment is beneficial for patients with AIS (Li et al., 2017). This study showed that the gray matter volume of the right anterior central gyrus, right central sulcus, right superior frontal gyrus, right middle frontal gyrus, and right inferior frontal gyrus in patients with AIS increased after DZXI treatment. Infarctions in these regions are associated with neurological and cognitive dysfunction (Galovic et al., 2013; Cheng et al., 2014; Wu et al., 2015; Henri-Bhargava et al., 2018; Parnaudeau et al., 2018; Zanto and Gazzaley, 2019; Zhu et al., 2019). Furthermore, DZXI treatment restored or reduced the volume of gray matter in specific areas such as the frontal cortex, which is a key area involved in cognitive dysfunction. In addition, DZXI treatment regulated the mitochondrial electron transport process, and the level of cytochrome C oxidase subunit 2 was significantly increased and protected the stability of neuronal mitochondria.

Among the studies retrieved in the present study, there are two articles about Centella asiatica (CAW), which is a plant that used in traditional Chinese medicine to enhance memory and improve cognitive function (Kapoor, 1990; Wattanathorn et al., 2008; Dev et al., 2009; Shinomol et al., 2011; Sirichoat et al., 2015; Gray et al., 2016; Umka Welbat et al., 2016; Chaisawang et al., 2017). In patients with epilepsy, long-term use of the current antiepileptic drugs cannot improve cognitive function (Ortinski and Meador, 2004; 77; Santulli et al., 2016). When CAW (Centella asiatica) is used to treat epileptic patients, it can not only alleviate seizures, but it also improves related memory disorders. The use of CAW before seizures has antiepileptic activity, which can restore the level of synaptophysin and mitochondrial function, reduce neuronal damage, and improve cognitive dysfunction. Therefore, natural medications are effective in treating cognitive dysfunction related to epilepsy. In conclusion, the natural product CAW may be beneficial for the treatment of epilepsy and related cognitive dysfunction.

In a mouse model of high-fat diet (HFD), the antioxidant activity of Actinidia arguta (CFAA) protected against HG-induced neurotoxicity and improved insulin resistance. At the same time, it was observed that the cognitive impairment was also improved through the reduction of oxidative stress and the enhancement of mitochondrial activity. CFAA can be used to treat neurodegenerative diseases caused by HFD.

Many studies on AD treatment have focused on natural products (Jeon et al., 2019). The present study collected five articles on the treatment of AD in patients with neurodegenerative dementia. Tetramethylpyrazine (TMP) from Ligusticum chuanxiong is a calcium antagonist with a strong neuroprotective effect in cerebral ischemia models (Chang et al., 2007). In rat models of Parkinson’s disease, TMP also has neuroprotective effects on dopaminergic neurons (Lu et al., 2014). In the AD mouse model of this study, after TMP treatment, mitochondrial proteins changed significantly, electron transport chain function improved, ATP levels increased, and synaptic dysfunction also improved.

The Ca²⁺ homeostasis in mitochondria is necessary to maintain normal neuronal function (Moreira et al., 2010). The protective effect of Ginkgolide K (GK) from Ginkgo biloba (a natural metabolite) on neuronal cells can promote neuronal cell survival (Liu et al., 2018), regulate mitochondrial function to exert a prosurvival effect (Ma et al., 2014; Zhou et al., 2017), inhibit MCU expression, reduce the Ca²⁺ level in the mitochondria, and prevent apoptosis.

Accumulation of Aβ in the brain is another important pathological feature of AD (Moon et al., 2012; Selkoe, 1994; Mancuso et al., 2009). Enhancement of mitochondrial homeostasis can offset Aβ protein toxicity and aggregation (Sorrentino et al., 2017), and Red ginseng (RGE) treatment can significantly restore impaired mitochondrial respiratory capacity and prevent mitochondrial fusion and division imbalance during Aβ-induced mitochondrial dysfunction. Simultaneously, RGE improved mitochondrial dysfunction and adult hippocampal neurogenesis, effectively preventing cognitive dysfunction in AD. The protective effect of RGE on mitochondrial function can reduce neuroinflammation. Therefore, RGE can promote AD therapy by protecting the neurons.

Rhein can improve mitochondrial function (Shin et al., 2019). Rhein activates SIRT1/PGC-1α, and mitochondrial biogenesis may be the key mechanism triggering the mitochondrial antioxidant defense system. After treating with Rhein, the expression level of SIRT1 and PGC-1α in the hippocampus of mice was significantly upregulated together with that of NRF1, which demonstrated that Rhein improved the biogenesis of mitochondria in AD mice, restored mitochondrial dynamics, repaired damaged mitochondria, and inhibited the electron transport chain to produce reactive oxygen species, thereby synergistically relieving neuronal oxidative stress (Yin et al., 2021). Thus, Rhein may have a potential therapeutic effect in AD.

The mixture of Schisandra chinensis extract (SCE) and ascorbic acid (AA) can improve cognitive function by enhancing mitochondrial respiration and inducing the activity of synaptic plasticity regulatory proteins, thereby improving mitochondrial function and memory and alleviating AD and age-related memory decline (Jang et al., 2020).

Sepsis, a common neurological complication, is associated with multiorgan failure, high mortality (Cecconi et al., 2018), and short-term or long-term neurological dysfunction (Silva et al., 2020). To date, there is no clear treatment. (−)-Epicatechin (Epi) from Green tea can be used as a new adjuvant treatment to improve the neurological prognosis of patients with sepsis. Epi is a natural polyphenol substance with an effective neuroprotective effect that has been shown to cross the blood-brain barrier and directly act on neurons (Mandel et al., 2008; Cruz-González et al., 2016; Bernatova, 2018). No obvious side effects have been observed (Borges et al., 2017). Epi controls the quality of mitochondria by activating AMPK signaling in the SAE. Epi treatment can reduce the decline of cognitive function, prevent the loss of neuronal dendritic spines, and reduce neuronal damage, which are related to the improvement of mitochondrial quality and reduction of neuroinflammation.

Cognitive dysfunction in the normal physiological process of aging is accompanied by various physiological phenomena (Beard et al., 2016; d'Avila et al., 2018). In the process of aging, there is dysfunction of organelles, such as mitochondrial enlargement or breakage; dysfunction of the electron transport chain; oxidative damage of mitochondrial DNA (Santos et al., 2013; Lores-Arnaiz et al., 2016). These processes may be important cell targets to protect against the cognitive dysfunction caused by aging. Trans-cinnamaldehyde (CIN) and ellagic acid (ELA) have been shown to inhibit oxidative stress, inflammation, apoptosis, and necrosis in many pathological models (Rajamani et al., 2015; Qi et al., 2016; Absalan et al., 2017; Firdaus et al., 2018; Rahimi et al., 2018). In this study, the combined treatment with ELA and CIN had a stronger and consistent effect on cognitive dysfunction in rats. Combined treatment can improve cognitive dysfunction induced by aging by inhibiting inflammation, protecting the mitochondrial function of the prefrontal cortex, and inhibiting the apoptosis signaling axis.

The main pathogenesis of vascular dementia (VD) includes chronic cerebral hypoperfusion (Damodaran et al., 2019), synaptic disorders (Sun, 2018), axonal abnormalities (Kalaria, 2018), hippocampal neuron loss (Jiang et al., 2019), and white matter vascular changes (Hase et al., 2019), which ultimately lead to cognitive impairment and dementia. The mitochondria are the main organelles involved in ischemia (Lv et al., 2017). Mitochondrial dysfunction in the brain plays an important role in the pathogenesis of VD. The SMYZD (which includes many Chinese botanical drug ingredients), can improve mitochondrial function, energy metabolism, and chronic cerebral perfusion insufficiency by activating the AMPK/PPARα/PGC-1α/UCP2 signaling pathway, which can improve mitochondrial structure and alleviate pathological damage in the rat brain. Anti-apoptotic and antioxidant properties, neurogenesis, and inhibition of mitochondrial dysfunction could exert these effects (Rajabian et al., 2019).

A previous study found that depletion of neuronal specific protein cell-cycle exit and neuronal differentiation 1 (CEND1) could lead to mitochondrial dysfunction, thereby causing cognitive dysfunction, and overexpression of CEND1 could improve cognitive dysfunction (Xie et al., 2022). It is unclear how natural products improve mitochondrial function under conditions of cognitive dysfunction, warranting further research to benefit the clinical treatment of cognitive dysfunction. Mounting evidence shows that the abnormality of mitochondrial dynamics generally precedes the hallmarks of pathology (Wang et al., 2021). Therefore, proper regulation of mitochondrial dynamics may be beneficial to AD patients.

The present study has limitations. The effect of natural products on mitochondria under conditions of cognitive dysfunction may not have been discussed comprehensively because we included few studies. Therefore, in the future, the inclusion criteria should be reconsidered and the mechanism of mitochondrial dysfunction in cognitive dysfunction should be discussed more comprehensively.

Overall, the mechanism underlying the effects of natural products on mitochondria is multileveled. The natural products used in clinical treatment are not only single botanical drugs but have multiple forms of composite applications. Whether there is drug interaction when they are used in combination remains to be determined. Therefore, metabolite botanical drugs, single botanical drugs, formulas, and combination of Chinese and Western medicine remain to be fully investigated to facilitate future clinical composite applications.

It is difficult for existing treatments to prevent the occurrence of cognitive dysfunction in neurodegenerative diseases; natural products may be a new therapeutic option. However, as natural botanical drugs are used for treatment, their mechanisms remain to be verified. The clinical use and in-depth research of natural products, especially the unique advantages in the field of cognitive impairment related to mitochondrial dysfunction, may create a new emphasis for drug research and the development of treatments for cognitive dysfunction-related diseases in the future.