Flavanoids isolated from various sources induced mitochondrial protection and improved mitochondrial function in PD by upregulating the production of ATP, and ROS, and maintaining the mitochondrial membrane potential and activity of mitochondrial complexes. The dicarbonyl compound methylglyoxal (MG) has been shown to be linked to PD development by inducing mitochondrial dysfunction (Bakala et al., 2012). Exposure of SH-SY5Y cells to MG caused decreases in cell viability, intracellular ATP, and mitochondrial membrane potential. The flavonoid naringenin is extracted from the pericarp of Citrus reticulata Blanco, known as 5,7-dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydrochromen-4-one. It is one of the most important polyphenolic flavanones and has been reported to have neuroprotective effects in PD possessing potent free radical scavenging properties (Lou et al., 2014). SH-SY5Y cells were pretreated for 2 h with naringenin (at 10–80 μM) and then challenged with MG at 500 μM for 24 h. Naringenin significantly increased MMP, ATP, and complex I and V activity, and attenuated the effects on mitochondrial function and the redox environment (de Oliveira et al., 2019). In another study, 80 μM Naringenin treatment in paraquat-induced SH-SY5Y cells resulted in increased cell viability, reduced oxidative stress, elevated MMP, and higher cellular ATP levels. In paraquat-induced rats, 40 mg/kg naringenin treatment resulted in significant neuroprotection against paraquat -induced behavioral deficits, oxidative stress, mitochondrial dysfunction, and astrocytosis (Ahmad et al., 2021). Calycosin, an isoflavonoid extracted from Astragalus membranaceus. , has been revealed to exhibit neuroprotective functions against cerebral ischemia and reperfusion-induced neurological injury, high glucose-induced oxidative stress and neuroinflammation, as well as neuronal apoptosis in earlier studies (Wang and Zhao, 2016; Hsu et al., 2020). Chaouhan et al. (2022) reported that calycosin administration increased ATP and MMP. Flies feed with 100 μM calycosin exhibited significant resistance against paraquat-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, depletion of dopamine content. Nobiletin is a natural polymethoxylated flavone. The disruption of mitochondrial respiratory complexes I-IV and the enhancement of ROS induced by lipopolysaccharide were ameliorated by nobiletin pretreatment, which also enhanced MMP in BV-2 microglial cells (Qi et al., 2019). Silibinin is a flavonoid extracted and isolated from the fruit of Silybum marianum (L.) Gaertn and has been widely used to exploit drugs for the treatment of diseases. Previous studies showed that silibinin could potentially exert protective effects against neuronal diseases including PD (Kujawska and Jodynis-Liebert, 2018). Silibinin restored MMP decline in mitochondrial respiration (Liu et al., 2021b). Baicalein, 5, 6, 7-trihydroxyflavone, is a flavonoid and is mainly derived from the root of the herb Scutellaria baicalensis Georgi, which is a well-known traditional Chinese medicine (Kuang et al., 2017). Baicalein has neuroprotective effects in PD models by exerting anti-inflammatory, anti-apoptosis, and antioxidative effects. In previous studies, it has been manifested that baicalein protected PC12 and SH-SY5Y cells against neurotoxicity induced by several toxic substances and ameliorated the neurotoxicity in rats (Mu et al., 2009; Zhang et al., 2012). It has been reported that 10 μM baicalein increased cell viability and restored mitochondrial function in SH-SY5Y cells. Baicalein administration (5 mg/kg) prevented rotenone-induced behavioral deficits, dopaminergic neuronal loss, and mitochondrial dysfunction in mice by restoring mitochondrial disorders of MMP decline. Hyperoside, which is a flavonoid glycoside, maintained MMP and ROS and improved mitochondrial function (Kwon et al., 2019). Quercetin (3,5,7,30,40-pentahydroxyflavone), found in Bupleurum chinense or Crataegus pinnatifida, has been proven to have neuroprotective and cognitive enhancing effects in different brain injury models (Selvakumar et al., 2012). A recent study reported that administration of quercetin (10 mg/kg) reduced aluminum-induced oxidative stress including decreasing ROS production and increasing mitochondrial superoxide dismutase (Sharma et al., 2016).

In addition, advanced glycation end products (AGEs) ligate to the receptor of AGEs (RAGE), improving activation of the transcription factor NF-κB, which may be involved in the development of neurodegenerative diseases (Qin et al., 2009). Myricitrin, a flavanoid contained in the root bark of Myrica cerifera, alleviated MG-induced dysfunction of mitochondrial bioenergetics, including an increase in ATP and MMP and a decrease in ROS at concentrations of 1 and 10 μm, and the possible mechanism is through inhibiting the AGE/RAGE/NF-κB pathway (Wang et al., 2014). Icaritin, a flavonoid extracted from Epimedium sagittatum maxim, reversed the decline in the levels of ATP, ADP, inosine, and citric acid in the substantia nigra of PD mice induced by MPTP. Icaritin improved the levels of SDHA, VDAC and ATP5B, which are closely related to mitochondrial respiration and energy supply (Wu et al., 2021).

In previous studies, various phenols and polyphenols exerted potent mitochondrial protection effects, such as resveratrol, mangiferin, curcumin, tea polyphenols, etc. Resveratrol is a natural polyphenolic compound sustained in a variety of plant species, such as Veratrum grandiflorum and Polygonum cuspidatum. It has been reported that resveratrol has potent potential for PD therapy via multiple mitochondria-related pathways (Yadav et al., 2022). The functional impacts of resveratrol on mitochondrial bioenergetics included a decrease in ROS, an increase in complex I and citrate synthase activities, basal oxygen consumption, mitochondrial ATP production, and an attenuated loss of MMP (Ferretta et al., 2014; Lin et al., 2018; Wang et al., 2018). Mangiferin is the primary polyphenol component of Mangifera indica L., possessing neuroprotective effects in PD. Mangiferin (20 μg/mL) pretreatment of rotenone- or MPTP-treated cells resulted in a higher MMP and significantly enhanced ATP levels in SK-N-SH neuroblastoma cells and a PD mouse model (Kavitha et al., 2014; Wang et al., 2022). Demethoxycurcumin (a natural derivative of curcumin), paeonolum and α-Arbutin, which are extracted from Curcuma longa, Ericaceae species, and Moutan cortex, respectively, have been shown to prevent MMP loss and ROS production (Lu et al., 2015; Ramkumar et al., 2017; Ding et al., 2020). In addition, Sativex^® (a mixture of 9-tetrahydrocannabinol and cannabidiol) significantly increased mitochondrial complex II activity and complex IV protein levels in mice (Khatri and Juvekar, 2016). Oleuropein, isolated from Fraxinus rhynchophylla, plays a role as a protective molecule against glutamate-induced mitochondrial dysfunction by regulating ATP and ROS levels (Kim et al., 2018). Additionally, Parkin deficiency is able to trigger mitochondrial dysfunction and dopaminergic neuronal loss (Lim and Ng, 2009). Polydatin, a nonglycosylated derivative of resveratrol extracted from grapes, protected mitochondrial function by increasing MMP and decreasing ROS in cells exposed to rotenone or knocked down Parkin (Bai et al., 2020). Putative kinase 1 (PINK1), linked to familial Parkinson’s disease, is known to affect mitochondrial function (Kim et al., 2012). Curcumin is an active natural polyphenolic compound extracted from rhizomes of C. longa, which is widely used. It has been reported that curcumin has multiple pharmacological effects, including the ability to inhibit the key characteristic features of PD such as ROS production, apoptosis, and cognitive deficits in cell cultures and animal models (Yang et al., 2005). In a recent study, it was shown that curcumin at different doses (50, 100, and 200 mg/kg) could significantly rescue complex II activity in mice that were given chronic administration of rotenone for 3 weeks and had significant alterations in mitochondrial enzyme complex activity (Khatri and Juvekar, 2016). The PINK1 gene plays a vital role in the maintenance and regulation of healthy mitochondria, and mutations in the PINK1 gene result in an autosomal recessive form of early-onset PD (Schapira AH et al., 1998). Subsequently, it was also reported that curcumin at a concentration of 2 μM increased MMP and spare respiratory capacity in paraquat-treated PINK1 siRNA and control SH-SY5Y cells (van der Merwe et al., 2017).

Several triterpenoids are capable of repairing the function of mitochondrial bioenergetics, including ginsenoside Re, ursolic, celastrol and mogroside V. Ginsenoside Re is one of the primary biologically active components of ginseng. Ginsenoside Re enhanced NO production and was capable of reversing the deficit in complex IV activity in PINK1 null cells by increasing LRPPRC, Hsp90, and Hsp60 levels, which are mitochondria-related complex IV assembly factors (Kim et al., 2012). Ursolic acid, a pentacyclic triterpenoid carboxylic acid, is found in many plant species. In rotenone-induced damage rats, treatment with ursolic acid at 5 and 10 mg/kg prevented inhibition of mitochondrial complex I activity in the mid-brain (Peshattiwar et al., 2020). Celastrol, a natural triterpene, protected SH-SY5Y cells from rotenone-induced MMP loss and ROS production (Choi et al., 2014). SIRT3 is present in the mitochondria and participates in multiple mitochondrial functions, including maintaining ATP levels (Ahn et al., 2008). Mogroside V, as a bioactive triterpene, recovered ROS and increased MMP, ATP production and the oxygen consumption rate in a dose-dependent manner, which may be associated with SIRT3 upregulation (Luo et al., 2022).

Treatment with the phenylethanoid glycoside echinacoside significantly attenuated the MMP decrease induced by 6-hydroxydopamine (6-OHDA) in PC12 cells (Wang et al., 2015). Astragalus polysaccharide is one of the main active ingredients in astragalus. Astragalus polysaccharide maintained MMP and ROS and improved mitochondrial function (Liu H. et al., 2018). Additionally, cordycepin (3′-deoxyadenosine) is the main bioactive ingredient isolated from Cordyceps militaris. It effectively preserves mitochondrial function by increasing MMP, ATP content, and complex I activity and decreasing ROS levels (Zhang et al., 2021).

Pretreatment of cells with 50 nM anthraquinone, extracted from edible fungi Pleurotus ostreatus, reversed the decrease in MMP induced by 6-OHDA (Bindhu et al., 2020). Treatment with 5 μM embelin resulted in a time-dependent enhancement of the basal oxygen consumption rate and ATP production in rat N27 cells (Rao et al., 2020).

Many plant extracts restored MMP and decreased mitochondrial depolarization, including the extracts of Calyptranthes grandifolia leaves (Kich et al., 2016) and the seaweeds Sargassum muticum, Codium tomentosum, and Ulva compressa (Silva et al., 2018). The extracts of Eucommia ulmoides, Zizyphus spinachristi fruits and Citrus bergamia fruits restored both MMP and ROS (Kwon et al., 2014; Singh et al., 2018; Ferlazzo et al., 2020). Extracts of Acanthopanax senticosus and Ganoderma lucidum reversed mitochondrial membrane potential collapse and ATP depletion caused by MPTP (Liu S. M. et al., 2018; Ren et al., 2019). Bacopa monnieri L. has been proven to have neuroprotective effects, and the standardized extract also plays a role by targeting mitochondrial respiration. Pretreatment with a standardized extract of Bacopa monnieria maintained complex I activity in SK-N-SH cells and complexes II-III activity in the mouse striatal region and prevented MMP loss and ROS production (Singh et al., 2012, 2013; Hosamani et al., 2016). Tomato seed extracts efficiently restored ROT-induced activity loss of complexes I-II (in the hippocampus) and complexes II-III (in the striatum) (Gokul and Muralidhara, 2014). Rao et al. (2016) studied the neuroprotective efficacy of saffron methanolic extract and its bioactive constituent crocin. They both increased the activity of complexes I-III (Rao et al., 2016). Supplementation of the ethyl acetate extract of Morinda citrifolia significantly augmented the activity of complex I by 22% and complex IV by 23% compared to only ROT-treated rats (Kishore Kumar et al., 2017). The standardized extract of Centella asiatica ECa233 (30 mg/kg) protected against the inhibition of complex I and an increase in ROS (Teerapattarakan et al., 2018). Selaginella delicatula extract restored rotenone-induced perturbations in the activity levels of complexes I-II, MMP and activity of ATPases to normalcy among mice (Chandran and Muralidhara, 2013). Piper longum L. extract, containing two active alkaloids, reversed the reduction in MMP in MN9D cells caused by rotenone and protected mitochondrial complex I activity (Wang et al., 2016). Pretreatment with red clover (Trifolium pratense) extract and the individual isoflavone daidzein both decreased ROS levels and enhanced the oxygen consumption rate (de Rus Jacquet et al., 2021).

The flavonoid baicalein could also increase autophagic flux in rotenone-treated mice by increasing the LC3B-II protein level (Kuang et al., 2017). PTEN-induced PINK1 and Parkin, the two PD-associated genes, are involved in the selective removal of damaged mitophagy (Geisler et al., 2010). Silibinin promoted clearance of the toxic effects of damaged mitochondria. MPTP-injected mice were protected against dopaminergic neuronal loss by oral administration of silibinin (280 mg/kg), which increased the expression of PTEN-PINK1 and Parkin, suggesting mitophagy activation (Liu et al., 2021a). The level of p62, an essential mitophagy regulator that indicates the accumulation of damaged mitochondria, was observed to be dramatically increased in paraquat-exposed flies. However, calycosin treatment inhibited this effect. It also decreased the phosphorylation levels of S6K and 4EBP1, indicating mitophagy stimulation (Chaouhan et al., 2022).

Resveratrol regulated mitochondrial biogenesis and mitophagy in PD by regulating the PGC-1α, LC3-II, p62 protein-related pathways, etc. Resveratrol also promoted LC3-II accumulation, inhibited p62 expression and augmented autophagic flux, which was inhibited by rotenone in SH-SY5Y cells (Lin et al., 2014; Lin et al., 2018). A significant resveratrol (25 μM) -mediated increase in the PGC-1α transcriptional activity of downstream genes TFAM and COX 1, the mtDNA/nDNA ratio, and enhanced macroautophagic flux through upregulating LC3-II levels was observed in skin fibroblasts from PD patients (Ferretta et al., 2014). Resveratrol at a concentration of 20 μM promoted LC3-II accumulation, inhibited p62 expression and augmented autophagic flux, which was inhibited by rotenone in SH-SY5Y cells (Lin et al., 2014; Lin et al., 2018). Vanillic acid is a phenolic compound found in various plants and fruits. Its treatment resulted in significant increases in the mRNA expression of PGC-1α and TFAM, and treatment with 300 µM for 24 h significantly elevated the mtDNA copy number and mitochondrial mass of SH-SY5Y cells (Ay, 2022). Urolithin A, a natural compound produced by gut bacteria from ingested ellagitannins and ellagic acid, decreased p62 protein levels and increased LC3-II and other related protein levels of Parkin and PINK1, regulating mitophagy (Qiu et al., 2022). Polydatin increased the expression of LC3-II, indicating that autophagic flux was augmented by polydatin (Bai et al., 2020).

Ursolic acid caused a prominent upregulation of COX1, the downstream gene of PGC-1α, in treated rats at a dose of 10 mg/kg, manifesting the promotion of mitochondrial biogenesis (Peshattiwar et al., 2020).

Pretreatment with the alkaloids piperine and piperlonguminine upregulated LC3-I/II in neurons compared to those without pretreatment, implying an increase in mitophagy (Wang et al., 2016). Nuclear factor erythroid 2-related factor 2-keap1 signaling pathways function to promote mitochondrial biogenesis and cell proliferation (Barone et al., 2011). The alkaloids nicotine and caffeine played a role in the activation of the nuclear factor erythroid 2-related factor 2-Keap1 and PGC-1α signaling pathways, thus regulating mitochondrial biogenesis (Zhou et al., 2019).

Embelin, a natural benzoquinone compound, increased mtDNA levels in a dose- and time-dependent manner in N27 cells. It also caused a substantial increase in the mitochondrial biogenesis regulators of pAMPK, SIRT1, PGC1α and mRNA levels of its downstream targets (Nrf 1/2 and TFAM) (Rao et al., 2020).

Incubation of PC12 cells with alkaloid component extracts from Huperzia selago and Diphasiastrum complanatum for 24 h evoked significant upregulation of the expression of the gene for DNA polymerase γ (Polg), which is responsible for replication of mtDNA and its repair processes (Lenkiewicz et al., 2016). Ginseng total protein administration led to an increase in mtDNA levels and supported mitochondrial biogenesis in PINK1^B9-mutated Drosophila (Liu et al., 2020). Theobroma cocoa extract at a concentration of 10 μg/mL produced significant upregulation of PPARγ, PGC1α, Nrf2, TFAM, and COX4 proteins in 1-methyl-4-phenyl-1,2,3,6- pyridine (MPP⁺)-treated SH-SY5Y cells, mediating mitochondrial biogenesis (Chidambaram et al., 2020). Supplementation with Artemisia argyi extract increased LC3B expression in a dose-dependent manner in comparison with cells treated with MPP⁺ alone (Wu et al., 2022).

Silibinin administration to MPTP-treated mice restored mitochondrial dynamic disorder by decreasing Drp1 expression and increasing Mfn1 expression in the hippocampus (Liu et al., 2021b). Quercetin attenuated aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation and restored the size of mitochondria to normality in the aluminum-treated rat hippocampus, improving mitochondrial integrity and function (Sharma et al., 2016).

Resveratrol pretreatment reversed high percentages of short and fragmented mitochondria in rotenone-exposed SH-SY5Y cells (Lin et al., 2018). Oleuropein, a polyphenolic compound extracted from F. rhynchophylla, amended a glutamate-induced mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria, regulating the phosphorylation of Drp1 at amino acid residue serine 637 (Kim et al., 2018). MPTP promoted Drp1 translocation to mitochondria. However, mangiferin (10 and 40 mg/kg) markedly inhibited this effect to prevent MPTP-induced excessive mitochondrial fission with reversed expression of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1 and p62, and mitigated mitochondria with a disrupted and swollen structure, vague mitochondrial cristae, and condensate matrix (Wang et al., 2022).

Treatment with 0.1% standardized methanolic extract of Mucuna pruriens seeds significantly reduced the number of damaged, swollen and clearly fragmented mitochondria in presynaptic boutons of antennal lobes of PINK1^B9 mutant flies compared with untreated mutants (Poddighe et al., 2014). 4-Hydroxyisophthalic acid is a bioactive component extracted from the roots of Decalepis hamiltonii. Fragmented mitochondrial cristae caused by paraquat exposure could be markedly reduced in the brains of flies fed 4-hydroxyisophthalic acid (Niveditha and Shivanandappa, 2018). Pretreatment with cocoa (10 μg/mL) extract downregulated the expression of mitochondrial Fis1 and upregulated the expression of Mfn2 proteins to balance mitochondrial dynamics in SH-SY5Y cells (Chidambaram et al., 2020). Artemisia leaf extract downregulated mitochondrial fission proteins (Drp1 and p-Drp1) and protected the mitochondria (Wu et al., 2022).

Baicalein inhibited the rotenone-induced increase in caspase-3 activity and significantly prevented rotenone-induced cleaved caspase-3 protein expression in mice (Kuang et al., 2017). Quercetin significantly reduced the Bax/Bcl-2 ratio and prevented the release of Cyt-c and subsequent activation of caspase-3, protecting the hippocampal region of the rat brain (Sharma et al., 2016). Pretreatment with naringenin increased the antiapoptotic protein Bcl-2 while decreasing the proapoptotic protein Bax and inhibited the MG-triggered release of Cyt-c from the mitochondria to the cytosol in SH-SY5Y cells. Meanwhile, it also significantly attenuated proapoptotic enzyme caspase-3/9 activation (de Oliveira et al., 2019). In addition, calycosin supplements alleviate paraquat -induced neurodegeneration by suppressing JNK phosphorylation and caspase-3 activation, which is responsible for DA neuronal cell death in exposed organisms (Chaouhan et al., 2022).

Glutamate treatment induced a decrease in Bcl-2 and an increase in Bax compared to control HT-22 cells. However, pretreatment with oleuropein maintained Bax/Bcl-2 expression levels in HT-22 cells exposed to glutamate treatment (Kim et al., 2018). Mangiferin prevented the increase in the expression of cytosolic Cyt-c and caspase-3/9 observed in rotenone -treated SK-N-SH cells (Kavitha et al., 2014). Green tea polyphenols increased the dysfunction of the mitochondrial apoptosis-related protein Bcl-2 and decreased Bax and caspase-3. When neurons were incubated with siBcl-2, the neuroprotective effect was abrogated (Cong et al., 2016). In rotenone-treated SH-SY5Y cells, the expression of Bax, Bad, caspase-3, caspase-6, caspase-8, and caspase-9 in mitochondria and Cyt-c in the cytosol was increased, whereas the distribution of Bcl-2, Bcl-xL and Cyt-c in mitochondria was significantly decreased. Pretreatment of cells with demethoxycurcumin gradually restored the excessive expression of these proteins (Ramkumar et al., 2017).

Caspase 3 activity and Cyt-c release into the cytosol were found to be decreased following dose-dependent treatment with mogroside V, indicating that mogroside V inhibited mitochondrial apoptosis (Luo et al., 2022).

Astragalus polysaccharide played a role in MPTP-induced PD mice by increasing Bcl-2 and decreasing the expression of Bax, Cyt-c, pro-caspase-3, and caspase-3 protein significantly compared with the control group (Liu H. et al., 2018).

MN9D cells exposed to the alkaloids piperine and piperlonguminine prior to rotenone application had lower cytosolic Cyt-c levels than cells treated with rotenone only, which indicated that the apoptosis induced by rotenone was inhibited (Wang et al., 2016).

Isolongifolene is a novel tricyclic sesquiterpene compound isolated from the herb Murraya koenigii. The biochemical effects of mitochondrial apoptosis in rotenone-treated rats were mitigated by isolongifolene (10 mg/kg), which increased the expression of anti-apoptotic Bcl-2, reduced the expression of pro-apoptotic Bax, inhibited Cyt-c release from mitochondria, and reduced the activation of caspases (Balakrishnan et al., 2021).

Plant extracts also have outstanding effects on hindering mitochondrial apoptosis. Many natural product extracts regulated apoptosis by inhibiting the activity of caspase-3/9, including the water extract of the Edible bird’s nest (Yew et al., 2014), ethanol and hexane extracts of C. grandifolia leaves (Kich et al., 2016), extracts of seaweeds (S. muticum, C. tomentosum, Padina pavonica, U. compressa) (Silva et al., 2018), and extracts of Echium amoenum petals (Sadeghi et al., 2018). Ganoderma lucidum extract and Z. spinachristi fruit extract suppressed the activation of caspase-3/9 and Cyt-c release from mitochondria into the cytoplasm (Singh et al., 2018; Ren et al., 2019). In addition, many plant extracts significantly upregulated the level of anti-apoptotic Bcl-2, downregulated the level of pro-apoptotic Bax and caspase-3/9 and blocked Cyt-c release into the cytosol, thereby alleviating neuronal loss, including the root bark extract of Paeonia suffruticosa, stem bark extract of E. ulmoides, and fruit extract of M. citrifolia (Kim et al., 2014; Kwon et al., 2014; Kishore Kumar et al., 2017). Theobroma cocoa extract increased the expression of the antiapoptotic protein Bcl-2 (Chidambaram et al., 2020). Additionally, pretreatment with the methanol extract of Humulus japonicus (100 and 200 μg/mL) significantly decreased the expression of cleaved PARP, cleaved caspase-9 and cleaved caspase-3. Meanwhile, Cyt-c release from the mitochondria to the cytosol was also significantly suppressed (Ryu et al., 2017). The incubation of SH-SY5Y cells with 6-OHDA significantly upregulated Bax and p53 proteins as well as downregulated Bcl-2 protein and the activity of caspase-3, which were significantly counteracted by preexposure to bergamot juice at both 0.5% and 1% concentrations (Ferlazzo et al., 2020).