Environmental factors were largely reported as exposures, and included post-encephalitic infection, pesticides, heavy metals, and dietary exposure (De Miranda et al., 2022). The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered after observing symptoms of PD in drug-abusing patients who smoked pethidine analogs contaminated with MPTP (Langston et al., 1983); this discovery indicated that exposure to pesticides and other environmental chemicals could increase the risk of developing PD. An Agricultural Health Study found a positive correlation between the risk of PD and exposure to pesticides known to inhibit mitochondrial complex I or lead to oxidative stress (Tanner et al., 2011). MPTP and its active metabolite MPP⁺ have been widely used in experimental animals and cell models of PD, respectively. Epidemiological studies have shown that the risk of PD increased in individuals who used rotenone in agriculture or who lived in close proximity to areas where rotenone was used (Tanner et al., 2011). Rotenone exposure was shown to induce degeneration of dopaminergic neurons, neuroinflammation, α-syn accumulation, and other pathological and behavioral alterations in rodent models (Xue and Bian, 2015). Furthermore, rotenone can directly impair mitochondrial function by inhibiting complex I and altering mitochondrial transport. The role of environmental factors of in the pathophysiology of PD remains elusive. However, it is well known that environmental factors related to cellular phenotype can be regarded as cellular hallmarks of PD.

In addition to genetic and environmental factors, there is a significant association between PD and disorders of iron metabolism. Increased brain iron of PD patients suggests that the interaction between iron and melanin may promote oxidative neuronal damage (Ndayisaba et al., 2019). Mitochondria act as the major iron recipients (Cerri et al., 2019). Iron ions in the SN may catalyze the conversion of H₂O₂ to highly active hydroxyl radicals, generated during the breakdown of DA, which may lead to oxidative damage (Jiang et al., 2017). Ferroptosis is a regulated, iron-dependent cell death pathway that involves a decrease in glutathione peroxidase 4 (GPX4) activity and the accumulation of lipid peroxide (Mahoney-Sanchez et al., 2021). Ferroptosis has several characteristics similar to PD pathophysiology and has been confirmed to be involved in the pathogenesis of PD. Mice exposed to iron produced parkinsonian phenotypes with loss of neurons in the SN and depletion of DA in the striatum (Kaur et al., 2007). It is known that MPTP, rotenone, and paraquat can inhibit the activity of mitochondrial complex I, which is associated with iron deposition (Munoz et al., 2016). Furthermore, an iron chelator can reduce the toxicity of these neurotoxin. Studies have shown that iron-mediated oxidative stress can promote α-syn aggregation (Angelova et al., 2020), indicating a close relationship between oxidative stress, α-syn, iron, and PD.

The mitochondrion is the only organelle with its own genome (mtDNA) in the cell. mtDNA is composed of multiple copies of circular, double-stranded molecules; it encodes 13 essential polypeptides in the respiratory chain, 2 ribosomal RNAs, and 22 transfer RNAs that are essential for mitochondrial protein synthesis. mtDNA is continuously damaged, which can eventually lead to mutations and mitochondrial dysfunction. Although mtDNA deletions were detected in elderly control subjects, there was an age-related accumulation of deletions that was accelerated in the striatum of PD patients (Ikebe et al., 1990; Manfredi, 2006); this association indicated that the mtDNA deletions contributed to the pathological process of PD. Increasing research has observed accumulation of deletions, mutations, and rearrangements of mtDNA in animal models of PD and in PD patients. A high level of deleted mtDNA found in the SN dopaminergic neurons of idiopathic PD patients was related to respiratory chain dysfunction (Grunewald et al., 2016).

Specific mitochondrial haplogroups are associated with either a lower or higher risk of developing PD. A systematic investigation in 2003 found that haplogroups J and K were associated with significantly reduced risk of developing PD and that this protective effect may have been associated with the single-nucleotide polymorphism 10398G, a common variant in the ND3 subunit of complex I (van der Walt et al., 2003). A two-stage association study confirmed that haplogroups J, K, and T were associated with a reduction in risk of developing PD; however, the super-haplogroup HV was associated with an increased risk of PD. mtDNA polymerase gamma (POLG), encoded by nuclear DNA (nDNA), was shown to participate in the replication, synthesis, and repair of mtDNA (Filosto et al., 2003). Mutations in the POLG gene caused multiple mtDNA deletions and PD phenotypes. In summary, it can be speculated that mtDNA haplogroups may have an antagonistic effect and influence susceptibility to age-dependent neurodegenerative diseases.

Multiple lines of evidence suggest that pathological processes in PD may result from a combination of both genetic and environmental factors (epigenetic modifications). Such modifications may damage mtDNA and impair mitochondrial function, while older individuals who experience prolonged stress are more likely to experience multiple molecular changes, such as the release of endogenous neurotoxins, higher oxidative stress levels, and epigenetic modifications. Epigenetic modifications have been reported to induce a series of changes in gene expression and protein levels that result in mitochondrial abnormalities and neuronal apoptosis and lead to PD (Ndayisaba et al., 2019). Environmental stresses have been shown to trigger epigenetic changes that induce molecular variation and alter the normal function of loci or chromosomes (Billingsley et al., 2019). Growing numbers of studies support the role of epigenetic modifications in explaining expression differences at the mitochondrial level in PD. In addition, non-coding RNAs (ncRNAs) can regulate many genes at the transcriptional level, despite not being translated into proteins. Their functions have been detected in the mitochondria, while ncRNAs such as microRNAs (miRNAs) (Zhang et al., 2021), long non-coding RNAs (Kopp et al., 2019), and some circular RNAs (Shao and Chen, 2016) have been shown to play multiple roles in many of the underlying mechanisms of PD pathogenesis. Observations of various epigenetic changes in mtDNA have received considerable attention. Epigenetic modifications of mtDNA, such as methylation and hydroxymethylation, are related to various environmental factors (including oxidative stress, therapeutic strategies, and aging) that induce parkinsonism (Byun and Baccarelli, 2014). One study reported increased mtDNA serum concentrations in female PD patients and demonstrated detectable cytosine-phosphate-guanine (CpG) methylation sites in the mitochondrial epigenome in platelet-derived mtDNA (Sharma et al., 2021). Furthermore, histone modifications in mitochondrial impairment are associated with PD pathology. Genome-wide histone acetylation analysis in PD patients revealed increased acetylation at multiple histone sites (H2B, H3, and H4), with the most notable change observed for H3K27, strongly suggesting that abnormal histone modification and altered transcriptional regulation are involved in the pathophysiology of PD (Toker et al., 2021). Notably, epigenetic modifications can also be affected by dietary nutrients, resulting in dynamic changes over the lifespan of an organism (Milosevic et al., 2021). Overall, mitochondria are currently attracting an increasing amount of attention in the field of PD epigenetics, providing a potential strategy for PD.

Mitochondria are highly dynamic and mobile organelles, constantly undergoing membrane remodeling through fission, fusion, and turnover to maintain mitochondrial homeostasis and function. Due to neuronal polarity, there is continuous transportation and exchange of material between the cell body and the synapses. Mitochondria are also transported across the cell body and synapses to ensure that energy requirements are met between different subcellular compartments. Excessive mitochondrial fission is widely thought to be the cause of mitophagy, leading to dopaminergic neurodegeneration in PD models (Chen et al., 2021). It is believed that dysregulation of mitochondrial dynamics is linked with neuroinflammation through the induction of interleukin-10 (IL-10) and reduction of tumor necrosis factor-α (TNF-α) secretion (de Oliveira et al., 2021). In response to cellular stress, a pathway for mitochondrial antigen presentation (MitAP) triggers an autoimmune response through extraction of self-antigens from mitochondria via MDVs and presentation at the cell surface (Roberts and Fon, 2016); PINK1 and parkin, actively repress MitAP by inhibiting this pathway in dysfunctional mitochondria (Matheoud et al., 2016). In fact, persistent activation of microglia in the brains of PD patients has been demonstrated (Gerhard et al., 2006). In PD, parkin deficiency results in the accumulation of impaired mitochondria and increased MitAP, which triggers and exacerbates central and peripheral inflammation. The pathway for MitAP relies on PINK1 and parkin, providing a bridge between mitochondrial dynamics and neuroinflammation in PD.

Mitochondrial fusion and fission are regulated by several proteins. Mitochondrial fusion is mainly mediated by MFN1, MFN2, and OPA1 (Rodrigues and Ferraz, 2020). Mitochondrial fission is regulated mainly by cytoplasmic DRP1, fission1 (FIS1), and mitochondrial fission factor (MFF) (Zhou et al., 2020). Increased fusion or fission leads to mitochondrial elongation or fragmentation, resulting in impaired mitochondrial function. It is difficult to study mitochondrial morphology in PD patients because the ultrastructure of post-mortem brain tissue of PD patients are not well preserved; however, PD-related neurotoxins can cause DRP1-dependent mitochondrial fragmentation in vivo and in vitro, indicating that mitochondrial fusion and fission are involved in PD (Santos and Cardoso, 2012). Studies have shown that DJ-1 deficiency can cause mitochondrial fragmentation that can be rescued by PINK1 and parkin (Thomas et al., 2011). Notably, other research has indicated that PINK1 and parkin participate in the control of mitochondrial dynamics (Scarffe et al., 2014). α-Syn is localized to the mitochondria, has a direct effect on the regulation of mitochondrial morphology (Vicario et al., 2018), and affects mitochondrial axonal transport and synaptic function (Koch et al., 2015). Furthermore, LRRK2 and VSP35 are thought to regulate mitochondrial morphology and transport (Mir et al., 2018), suggesting that mutant genotypes associated with familial PD may represent the upstream mechanism regulating mitochondrial morphology and transport.

There are three main forms of autophagy: microautophagy, molecular chaperone mediated autophagy (CMA), and macroautophagy. Mitophagy is a form of macroautophagy, a selective degradation of impaired mitochondria that limits the accumulation of dysfunctional mitochondria in the cell. It is an essential process in maintenance of the health of mitochondria. Increasing evidence has shown that neurodegeneration is accompanied by abnormal mitophagy.

In 2008, researchers discovered the relationship between the PD-related protein parkin and mitophagy (Narendra et al., 2008); it is considered a milestone study of mitophagy. Several subsequent studies have shown that PINK1, another protein associated with PD, is also involved in mitophagy (Clark et al., 2021; Goncalves and Morais, 2021). The PINK1/parkin pathway is the most widely studied mechanism in mitophagy. Under normal conditions, PINK1 is rapidly degraded after cleavage by PARL in low levels on the surface of mitochondria. Dissipation of mitochondrial membrane potential caused by mitochondrial depolarization, protein misfolding, or ROS can impair this degradation process; dissipation is considered the main event that initiates of mitophagy, causing the accumulation of PINK1 on the surface of mitochondria and the recruitment of parkin (Wang et al., 2021b). PINK1 phosphorylates MFN2 and ubiquitin, which in turn causes recruitment of parkin (McLelland et al., 2018). Several proteins ubiquitinated by parkin on the OMM then form phosphoubiquitin chains, which recruit autophagy receptors and induce mitochondrial autophagy. Loss of PINK1 or parkin function causes significant mitochondrial disease and degeneration of dopaminergic neurons (Morais et al., 2014; Cartelli et al., 2018). Mitophagy mediated by PINK1 and parkin also involves changes in mitochondrial dynamics. Both MFN1 and MFN2 are targets of parkin and are marked for degradation (Gegg et al., 2013), which can inhibit mitochondrial fusion. Furthermore, mitochondrial fission facilitates mitophagy by producing smaller organelles that are more easily engulfed by autophagosomes. Excessive fission caused by loss of parkin or PINK1 can be countered by MFN2 and OPA1 or by dominant negative mutations of the fission protein DRP1 (Giannoccaro et al., 2017). Interestingly, the PINK1/parkin pathway can prevent mitochondrial movement and isolate damaged mitochondria before clearance. PINK1 was reported to phosphorylate mitochondrial motility related protein Miro and activate proteasomal degradation of Miro in a parkin-dependent manner (Shlevkov et al., 2016). Mitochondrial dysfunction and impairment of autophagy are key factors in the pathogenesis of PD. In addition to the PINK1/parkin pathway, LRRK2, α-syn, DJ-1, and other PD-related proteins have been reported to be involved in mitochondrial quality control or mitophagy, see Verstraeten et al.’s (2015) review. G2019S substitution of LRRK2 mutation weakened the interaction between parkin and DRP1, leading to interference with PINK1/parkin mitophagy (Bonello et al., 2019). DJ-1 promoted mitophagy to respond to oxidative stress, acting simultaneously with the PINK1/parkin pathway (Thomas et al., 2011). Mitophagy plays a crucial role in the pathogenesis of PD. Thus, a thorough study of how these genes are involved in the regulation of mitophagy is essential for understanding the pathogenesis of PD and for the development of new therapeutic strategies.

Mitochondrial-derived vesicles, first reported in 2008, is involved in a repair mechanism that transports damaged mitochondria or oxidized proteins (Neuspiel et al., 2008). MDVs are composed of a double membrane with a diameter of 70–150 nm; they bud off from the mitochondria. In contrast with mitophagy, the MDVs pathway handles mildly damaged mitochondria and is independent from mitochondrial depolarization, fission, and autophagy.

Two different types of MDVs have been studied extensively. The first type of MDVs is PINK1/parkin-dependent and targets cargo proteins directly to lysosomes (McLelland et al., 2016). Notably, this process acts independently from autophagy and the oxidized cargo protein is degraded directly in the lysosome (Soubannier et al., 2012). These MDVs act as a defense mechanism to reduce mild mitochondrial damage below the mitophagy threshold. To rapidly respond to ROS production and oxidative stress, a local PINK1/parkin pathway is activated for exporting damaged proteins to the lysosome; disruption of this pathway may influence the ability of mitochondria to remove oxidized proteins, potentially exacerbating mitochondrial dysfunction in PD (McLelland et al., 2014). The second type of MDVs is targeted from mitochondria to peroxisomes (Soubannier et al., 2012). The only protein known to be able to transport vesicles to peroxisomes is membrane anchored protein ligase (MAPL) reviewed in Sugiura et al. (2014). Research has shown that this process is associated with a reverse complex involved in the transport of cargo proteins from the endosome to the Golgi apparatus (Braschi et al., 2010). Interestingly, another PD-linked gene, VPS35, has been found in the reverse transcription complex with MAPL; it regulates the formation of MDVs and participates in directing MDVs to peroxisomes. MDVs mediate VPS35-dependent mitochondrial DRP1 turnover through VPS35-DRP1 interaction and PD-linked mutations in VPS35 cause the accumulation of DRP1, leading to fragmentation of the mitochondrial network (Wang et al., 2016). In general, MDVs-mediated mitochondrial quality control mechanisms ensure organelle homeostasis before triggering more mitochondrial degradations.

Mitochondria-associated membranes are a specialized domain that interface with 5–20% of the OMM and ER membranes (Wang et al., 2021a). The physical tethering of ER to mitochondria was confirmed through transmission electron microscopy in the early 1960s. The ER and mitochondria were connected by tethers at a physical distance of 10–25 nm (Csordas et al., 2006; Liu et al., 2022). Due to variation in the quantity and molecular composition of MAMs, they are considered dynamic structures. Increasing evidence has indicated that MAMs regulated several cellular processes, including Ca²⁺ homeostasis, phospholipid exchange, mitochondrial biogenesis, autophagy, and mitochondrial dynamics (Wu et al., 2016; Dia et al., 2020; Yeo et al., 2021).

Several PD-related proteins, such as α-syn, parkin, PINK1, DJ-1, VPS35, and LRRK2, have been confirmed to alter the ER-mitochondrial signaling and influence Ca²⁺ balance. Furthermore, PD-linked mutations have been shown to impair MAMs. Abnormally accumulated α-syn can alter the number of the ER-mitochondrial contact sites and alter the transport of Ca²⁺ (Paillusson et al., 2017); α-syn interaction with vesicle-associated membrane protein-associated protein B (VAPB) in the MAMs protein complex interferes with the contact between VAPB and tyrosine phosphatase interacting protein 51 (PTPIP51) of MAMs. α-Syn is localized to the MAMs. The aggregation of α-syn weakened the interaction between α-syn and MAMs, altering mitochondrial morphology and mitochondrial intracellular distribution, see the exciting review by Rowland and Voeltz (2012). α-Syn mutations can also impair tethering and weaken the association between mitochondria and the ER (Cali et al., 2019). It has further been suggested that aggregated α-syn represents the initiating factor that disturbs mitochondrial dynamics during the pathogenesis of PD. In addition, parkin knockdown has been shown to result in fragmented mitochondria and reduce the number of the ER-mitochondria contact sites in the SH-SY5Y cell model (Cali et al., 2013). DJ-1 overexpression increased the ER-mitochondria connection and DJ-1 knockout resulted in significant functional impairment of MAMs both in vitro and in vivo (Liu et al., 2019). Alterations of MAMs in different PD models are summarized exhaustively in Gomez-Suaga et al.’s (2018) review. Although MAMs function is impaired in PD, it is still unclear whether MAM dysfunction is the cause or effect of the pathogenesis of PD; however, it is clear that the dysregulation of MAM can facilitate neuronal death.

MicroRNAs (miRNAs) are ncRNAs, 18–25 bases in length, that serve as regulators that affect stability and translation of mRNA targets by directing RNA-induced silencing complex (RISC) to the 3′-UTR, more details see Bartel’s (2018) review. Increasing evidence has revealed the association between miRNA and the pathogenesis of PD (Rostamian Delavar et al., 2018). It has been reported that levels of several miRNAs are altered both in PD models and in the brain tissue of PD patients (Viswambharan et al., 2017; Rostamian Delavar et al., 2018). Most of the altered miRNAs in PD patients are directly associated with mitochondrial function reviewed in Sun et al. (2019).

It has been reported that miR-133b is downregulated in the midbrain of PD patients, which indirectly decreases the expression of vesicular monoamine transporter 2 (VMAT2) by downregulating paired-like homeodomain transcription factor 3 (Pitx3) and altering the expression of dopamine transporter (DAT) through the same process that alters VMAT2 expression (Hwang et al., 2009). However, MiR-137 and miR-491 have been shown to reduce DAT expression, thereby influencing neuronal DA transport in vitro (Jia et al., 2016). The altered expression of these miRNAs is also associated with oxidative stress in PD. MiR-27a and miR-27b were found to regulate mitochondrial quality control by inhibiting the expression of PINK1 (Kim et al., 2016). MiR-34b and miR-34c are downregulated in the SNpc of PD patients. MiR-34 was found to reduce neuronal viability through mitochondrial dysfunction and the production of ROS in vitro (Minones-Moyano et al., 2011; Polytarchou et al., 2020). Further studies have suggested that the reduction in expression of miR-34b and miR-34c is related to the expression of DJ-1 and parkin, although the underlying mechanism is still unclear (Polytarchou et al., 2020). According to reports, several miRNAs regulate the expression and accumulation of α-syn, such as miR-7, miR-34b/c, and miR-19a-3p (Consales et al., 2018; Zhou et al., 2019; Zhang et al., 2021); their alterations may promote α-syn-mediated neurotoxicity. Abnormal expression of miRNA can be triggered by long-term environmental stressors, such as oxidative stress, toxins, or pathogens that induce both physiological and pathological stress. The various environmental stresses that humans experience throughout their lives may alter transcriptional regulation, consequently inducing mitochondrial dysfunction and eventually lead to sporadic PD.

In 2015, researchers discovered a pomegranate-like structure with a diameter of about 2 μm outside of cells, named the “migrasome,” which formed on the retraction fibers of migrating cells (Ma et al., 2015). Mass spectrometry revealed that tetraspanins were enriched in migrasomes, and studies have confirmed the necessity of tetraspanins and cholesterol for migrasome formation through live-cell experiments and reconstituted membrane systems (Huang et al., 2019). When migrating cells were under mild mitochondrial stress, they disposed of impaired mitochondria through mitocytosis, which is a migrasome-mediated mitochondrial quality control process (Jiao et al., 2021). Under normal conditions, inhibiting mitocytosis resulted in decreased mitochondrial membrane potential and respiratory function; enhancing mitocytosis had a protective effect, preventing the loss of mitochondrial membrane potential and the impairment of mitochondrial respiration induced by mitochondrial stressors (Jiao et al., 2021). In vivo studies confirmed that mitocytosis was beneficial for maintaining a healthy mitochondrial network in highly migratory neutrophils. Although migrasomes have been detected in the infarcted brain parenchyma of stroke patients and described as a new mechanism in the pathophysiology of acute stroke, further research regarding these structures is needed (Schmidt-Pogoda et al., 2018). In the aged brain, subventricular zone neurogenesis is reduced due to a decrease in the number of neural stem cells (Capilla-Gonzalez et al., 2014). Because the glial tube is maintained by neuroblast secretion of slit guidance ligand 1 (Slit1), a small number of neuroblasts may not produce enough Slit1 to maintain the most effective migration route (Kaneko et al., 2010). It is unclear whether mitocytosis is involved in the pathogenesis and progression of PD, and further research into mature dopaminergic neuron migration and mitocytosis would be essential to the study of PD pathogenesis.

In 1972, gene therapy was initially described as a method of “using good DNA to replace bad DNA,” see Friedmann and Roblin’s (1972) review. With the rapid developments in science and technology, the basic principles of gene therapy persist, but the process has become more complex. The most common strategy is to use viral vectors, such as lentivirus and recombinant adeno-associated virus (AAV), to effectively target delivery of genetic material into cells to regulate the expression of specific genes. Several gene therapy targets have been identified in PD: restoration of DA synthesis, enhancement of neurotrophic support, and modulation of the interaction between different functional brain nodes. Gene therapy in PD is designed to target key elements in the mitochondrial pathway that prevent neurodegeneration. PGC-1α is a transcriptional coactivator that positively regulates expression of several genes required for mitochondrial biogenesis and antioxidant response; the level of PGC-1α is decreased in PD patients (Jo et al., 2021); therefore, PGC-1α has become a promising therapeutic target for neuroprotection in PD interventions. In addition, CRISPR-CAS9 gene editing technology can correct gene mutations that result in focal disease activity and may also alter the DNA of germ cells to protect offspring from familial PD, for more information refer to the two reviews by Yang et al. (2016) and Karimian et al. (2020).

During the progression of PD, neurons were shown to exhibit mitochondrial dysfunction with decreased production of ATP and reduced expression of the respiratory chain complex, coinciding with increased ROS generation. It is well known that damaged mitochondria produce greater amounts of ROS than healthy mitochondria. Furthermore, neuronal mitochondria are more vulnerable to oxidative stress and have a slow turnover (Yang et al., 2020). Free radicals produced by oxidative stress affect the structure and function of neural cells, which may disrupt antioxidant mechanisms and ultimately lead to neurodegeneration.

Resveratrol was reported to have antioxidant effects and improved movement disorders in a MPTP mouse model (Guo et al., 2016). Resveratrol has been shown in vitro to act through the AKT/GSK-3β pathway against MPP⁺ induced mitochondrial dysfunction and apoptosis (Xiong et al., 2020). Although coenzyme Q10 (CoQ10) is an antioxidant that has been shown to enhance the activity of complex I and II in the electron transport chain, a meta-analysis reported that CoQ10 supplementation did not slow down the functional decline of PD patients, nor did it provide any symptomatic improvement (Negida et al., 2016). Researchers have also proposed that only a certain subset of PD (“mitochondrial form of PD”) can benefit from CoQ10 treatment; it was reported that CoQ10 counteracted the neurotoxicity induced by MPTP and prevented the electron transfer from complex I to others (Cleren et al., 2008). Furthermore, compared with other untargeted antioxidants, MitoQ was more effective in preventing mitochondrial oxidative damage (Feniouk and Skulachev, 2017). It was demonstrated that MitoQ had a protective effect on 6-OHDA-induced mitochondrial dysfunction in PD models in vivo and in vitro; the possible mechanism involved PGC-1α-mediated increase of MFN2 expression (Xi et al., 2018). Saffron is considered to have multiple health-promoting effects. Saffron extracts and its bioactive components have antioxidant properties, which can restore the activity of antioxidant enzymes such as superoxide dismutase (SOD), glutathione S-transferase (GST), and catalase, increasing the level of glutathione and total thiol, reducing ROS, and providing a potential therapy for improving the motor symptoms of PD (Rahaiee et al., 2015; Inoue et al., 2021). N-acetylcysteine (NAC) is a powerful scavenger of free oxygen radicals, which keeps sulfhydryl groups in a reduced state and restores the level of neuronal glutathione (GSH) (Shahripour et al., 2014). Because the death of dopaminergic neurons is related to oxidative stress and GSH depletion, and it has been reported that normalization of GSH levels can reduce oxidative stress and cell death; therefore, regulating neuronal GSH metabolism has potential therapeutic significance for PD. Interestingly, some antioxidants, such as resveratrol and vitamin E, are able to regulate DNA methylation and histone acetylation by inhibiting DNA methyltransferase and histone deacetylase activity (Coupland et al., 2014; Li et al., 2021). Oxidative stress and mitochondrial dysfunction are closely associated with the pathophysiology of PD. Prevention of the formation of excessive ROS and antioxidant therapy to ameliorate mitochondrial function in a timely and effective manner represent promising strategies for treating PD.

Mitochondrial biogenesis involves complex processes and requires the joint participation of the mitochondrial genome and the nuclear genome to maintain mitochondrial homeostasis. The biogenesis of a large number of functional mitochondria may reduce the production of ROS. A genome-wide study showed that the expression of PGC-1α, the main controller of mitochondrial biogenesis, was reduced in PD models compared with controls, which confirmed the role of mitochondrial biogenesis in the pathogenesis of PD (Imam et al., 2013; Yazar et al., 2021). A recent study showed that parkin-knockout DA neurons had mitophagy defects that mainly resulted from mitochondrial biogenesis defects driven by parkin interacting substrate (PARIS) upregulation and subsequent PGC-1α downregulation (Pirooznia et al., 2020). In addition to regulating mitophagy, parkin is also involved in controlling mitochondrial biogenesis (Kumar et al., 2020). Therefore, inducing or improving mitochondrial biogenesis should be considered a therapeutic target of neuroprotective methods for the treatment of PD. Although other approaches can be targeted to regulate mitochondrial biogenesis, targeting of the AMPK-SIRT1-PGC-1α axis would be most important pathway to enhance mitochondrial biogenesis (Chandra et al., 2019). It has been demonstrated that the activation of PGC-1α had neuroprotective effects in different mouse models of PD. Bezafibrate, acting as pan-PPAR agonist, upregulated PGC-1α levels and exhibited protective effects in mouse models of neurodegenerative disease (Johri et al., 2012). In addition, recent research has confirmed that a dopamine D1 receptor agonist can ameliorate mitochondrial biogenesis in a rat model of PD, and D1 agonist-mediated effects were eliminated following D1 receptor antagonist treatment (Mishra et al., 2020). It is worth mentioning that mitochondrial transplantation by supplementing exogenous mitochondria is a promising strategy in PD, refer to this interesting review by Shanmughapriya et al. (2020).

Mitophagy is important to the pathophysiology of PD. An ultrastructural study showed mitophagy accumulation in neurons of Lewy body dementia (LBD) and PD patients (Hou et al., 2018). Parkin and PINK1 genes are the pivotal causes of autosomal recessive PD and intermediate mitophagy (Gan et al., 2022). Studies have shown that celastrol reduced dopaminergic neuron death in a PD cell model and inhibited neurodegeneration in a PD animal model through upregulation of PINK1 and enhanced mitophagy (Lin et al., 2020). A drug screening experiment used a high-throughput phenotyping system on dopaminergic neurons derived from iPSCs collected from PD patients with parkin or PINK1 mutations to identify four candidates that could effectively improve the clearance of damaged mitochondria through screening 320 compounds (Yamaguchi et al., 2020). Some of the candidates were validated as they were found to ameliorate motor deficits caused by PINK1 deficiency in Drosophila and to be effective in iPSCs derived from idiopathic PD patients with impaired mitochondrial clearance. Melatonin is present in high concentrations in the mitochondria, which can prevent the oxidation of cardiolipin and help to restore mitophagy in PD (Chu et al., 2013). In addition, activators of parkin and PINK1 and inhibitors of USP30 and USP14 present promising therapeutic strategies for enhancing mitophagy (Xiang et al., 2020; Luo et al., 2021). Enhancing mitophagy is a meaningful therapeutic approach in PD (Aman et al., 2020).

Mitochondrial therapeutics undoubtedly have a positive impact on PD progression. However, these approaches allow only for symptomatic treatment and do not prevent the severe disability and significant reduction in quality of life that occur at later stages of disease. Various therapeutic approaches focus on the possible mitochondrial etiology of PD, as changes in the pathophysiological network of mitochondria can lead to the disease; nonetheless, the exact mechanism of the interactions between these networks is not fully understood, see Borsche et al.’s (2021) review. Clinical trials for PD have had limited success to date, and there are still no effective neuroprotective therapies to suppress or slow down the progression of PD. Lack of success in clinical trials can be attributed to an incomplete understanding of the molecular pathways and targets in PD, the heterogeneity of patient populations, a lack of adequate biomarkers to monitor drug efficacy, distinguish patient subtypes, and limited understanding of the sequence in which different cellular mechanisms lead to neuronal loss, see Lang and Espay’s (2018) review. Furthermore, PD presents many challenges to therapeutic approaches, including the difficulty of introducing therapeutics into the brain, target specificity, potential inflammatory responses, safety concerns, tolerability for geriatric patients, ethical implications, and the mechanistic heterogeneity of the disease, refer to these reviews by Jarrin et al. (2021) and Vijiaratnam et al. (2021). A major challenge for any preventative therapy is that much of the mitochondrial dysfunction in the brain of PD patients may have already occurred before the point of diagnosis during the prodromal period, see the excellent review by Schapira and Tolosa (2010). A study published in Nature in 2021 was the first to simulate a model of prophase PD, as well as the first to show that simple damage to mitochondrial function could fully simulate the pathogenesis of PD in animals. This suggested that mitochondrial dysfunction occurs before the onset of PD and that targeting mitochondria may therefore potentially provide the opportunity to slow the progress of PD at the earliest possible stage (Gonzalez-Rodriguez et al., 2021). Therefore, one of the most critical challenges is the identification of biomarkers for the prodromal stages of PD, which would allow the earlier initiation of new therapeutic strategies.