Mitochondria are the main site of aerobic cellular respiration, and this is accomplished mainly by the mitochondrial respiratory chain. Mitochondrial respiratory chain, also known as the electron transport chain (ETC), consists of four complexes I, II, III, and IV. There are two known ETCs, one is the nicotinamide adenine dinucleotide (NADH) respiratory chain, NADH-complex I-coenzyme Q-complex III-cytochrome c (Cyto c)-complex IV-O2, and the other is the reduced flavin adenine dinucleotide (FADH2) respiratory chain, FADH2-complex II-coenzyme Q-complex III- Cyto c complex IV-O2. On this basis, the mitochondrial inner membrane respiratory chain enzyme system is further divided into five major groups: complexes I, II, III, IV, and complex V (ATPase) which is not part of the respiratory chain (Ahmad et al., 2021).

Resveratrol (RESV) (Zhang B. et al., 2019) and Curcumin (CUR) can increase Complex I and III activity and improve the respiratory chain and thus mitochondrial dysfunction. CUR also elevates the TCA cycle (Han et al., 2021) and restores the mitochondrial coupling process and the abnormal opening of the mitochondrial permeability transition pore.

As the end product of glycolysis, pyruvate is located at the intersection of glycolysis and the tricarboxylic acid cycle, and the Mitochondrial pyruvate carrier (MPC) located in the inner mitochondrial membrane transports pyruvate from the cytoplasm to the mitochondrial matrix (Taylor, 2017), abnormalities in MPC will affect the uptake and utilization of pyruvate by the mitochondria, thus affecting the normal function of the mitochondrial respiratory chain. The expression of peroxisome proliferator-activated receptor-g coactivator 1a (PGC-1α), MPC1, and MPC2 was increased by Artemether in db/db mice (Han et al., 2019). PDK1 is a kinase that inactivates pyruvate dehydrogenase (Klyuyeva et al., 2019), and Artemether treatment was found to reduce the level of mitochondrial protein PDK1, reverse the low expression of catalase, SOD2, and other antioxidant enzymes, and alleviate the redox imbalance in type 1 diabetes (T1D) DKD mice (Wang M. et al., 2019).

The mitochondrial complex III rapidly produces ROS in the sensitive area of antimycin A, and melatonin can act as a ROS scavenger. Studies have shown (Zhang et al., 2011) that melatonin can increase the expression of the complex I protein in db/db mice, reduce complex III activity, and damage mitochondria by affecting the balance of mitochondrial electron transport, leading to overproduction of ROS. Melatonin restores mitochondrial membrane potential in podocytes, dose-dependent elimination of Angiotensin II-induced ROS increase, and protects damaged mitochondria (Ji and Xu, 2016). In addition, Melatonin reduced the abnormal increase in ROS and inhibited the high expression of pro-apoptotic proteins [caspase-3, -9 and Bcl-2-associated X protein (Bax)], possibly due to a protective mechanism mediated by the 5-AMP-activated protein kinase (AMPK)/PGC-1α pathway (Satari et al., 2021).

The activity of antioxidant enzymes is sometimes also closely related to mitochondrial respiratory chain abnormalities. Purslane polysaccharide (Wang and Ye, 2018) and Jujuboside A (Zhong et al., 2022) both increase the activity of mitochondrial respiratory chain complexes and antioxidant enzymes, restoring damage caused by mitochondrial respiratory chain abnormalities as well as oxygen species (OS).

Abnormalities in the mitochondrial respiratory chain can lead to an abnormal increase in one of the final harmful products, ROS. The products of ROS mainly include to the single electron reduction product of O2, superoxide anion (O2-), and its derivatives hydrogen peroxide (H2O2), hydroxyl radical (OH-), and singlet state O2 (Ahmad et al., 2021). An increase in ROS production and/or a decrease in the ability to clear ROS for various reasons can lead to an increase in endogenous ROS, which can leads to a state of oxidative and antioxidant imbalance, that is, what we often call OS. Moreover, increased ROS leads to breakage of mtDNA and interferes with transcriptional synthesis, which affects the efficacy of ETC and leads to reduced ATP production; it also stimulates inflammatory factors and thus induces an inflammatory cascade response; increased ROS triggers autophagy in the mitochondrial pathway, activates apoptosis-related proteins, and triggers apoptosis in the mitochondrial pathway (Ruiz et al., 2013; Flemming et al., 2016).

Antioxidant enzymes can counteract the abnormal increase of ROS. Mn-SOD is one of the few antioxidant enzymes present in mammalian mitochondria. A study (Williams et al., 1998) provides direct evidence that reduced Mn-SOD activity in vivo is associated with increased mitochondrial oxidative damage and consequently altered function. As ROS scavengers, RESV can increase the activity of Mn-SOD and other mitochondria-associated peroxidases and thus reduce the damage caused by OS to mitochondria, and in addition, the expression of 8-OHdG in mtDNA and the accumulation of D-17 deletion in mtDNA are correspondingly reduced after RESV treatment (Kitada et al., 2011).

RESV Zhang T. et al. (2019), Berberine (BBR) (Qin et al., 2019), cyanidin-3-O-β-glucoside chloride (C3G) (Wei et al., 2018) can eliminate mitochondrial ROS and reverse the abnormal changes in mitochondria caused by OS. Inhibition of the NRF2/HO-1 pathway can alleviate OS, and both Notoginsenoside R1 (Zhang B. et al., 2019) and Obacunone (OB) (Zhou et al., 2019) can eliminate ROS through this pathway and attenuate the damage caused by OS. Astaxanthin (ASX) scavenges excess ROS as well as ROS-modified protein 4-hydroxy-2-nonenal (4HNE) from mitochondria in Normal human mesangial cells (NHMCs), and ASX inhibits the development of diabetic nephropathy by reducing mitochondrial damage through Inhibition of ROS production (Manabe et al., 2008). Curcumin inhibits protein kinase C-β(PKCβ)/p66Shc/NADPH oxidase and activates FOXO-3a to suppress OS in the mitochondrial pathway through a decrease in p66Shc levels in mitochondria (Altamimi et al., 2021).

Silent information regulator 1 (SIRT1) is a histone deacetylase dependent on nicotinamide adenosine dinucleotide (NAD⁺). Puerarin (PR) ameliorates varying degrees of mitochondrial damage under the ultrastructure of DN mice kidney tissue cells. Activation of the SIRT1/(forkhead transcription factor-O1) FOXO1 pathway would result in low OS in mitochondria. PR positively upregulates SIRT1/FOXO1 signaling pathway expression levels, significantly reducing the expression of inflammatory factors such as NF-κB, IL-6, and TNF-α. PR exerts antioxidant effects by increasing the activity of Mn-SOD and CAT. Above all, it improves mitochondrial dysfunction by alleviating OS and inflammatory response (Xu et al., 2016). It was found that the accumulation of ceramide could lead to elevated mitochondrial ROS. Myriocin, as an inhibitor of de novo ceramide synthesis, could reduce ceramide and subsequent ROS accumulation, and myriocin treatment could reduce vesicle expansion of mitochondrial cristae and maintain the stability of mitochondrial morphology, as observed under Electron Microscope (Woo et al., 2020).

OS and inflammation are closely linked and both contribute to the progression of DKD (Bruchfeld et al., 2016). To some extent, the inflammatory response is a kind of self-protection of the body, however, the long-term persistent inflammatory state is a harm to the body. The most studied and inextricably linked to mitochondrial dysfunction is the NOD-like receptor protein 3 (NLRP3) inflammatory vesicles, which are multiprotein complexes. There are multiple pathways for NLRP3 inflammatory vesicle activation, one of which is: being oxidized mtDNA fragments enter the cytoplasm via the mitochondrial permeability transition pore (mPTP) and then bind to NLRP3 and cyclic GMP-AMP Synthase (cGAS) to activate NLRP3 inflammasomes. A study has confirmed the key role of ROS in activating small inflammatory bodies in diabetic kidney disease (Shahzad et al., 2015). CUR Lu et al. (2018) and Icariin (Ding et al., 2022) both inhibit the activation of NLRP3 inflammasome.

The activation of NLRP3 further activates downstream inflammatory factors to aggravate kidney injury, and ROS, as one of the common activation pathways of NLRP3, his activation mechanism is gradually coming into the public view, but the current research reports on this area are few and not in-depth, and there are many anti-inflammatory herbs and active ingredients in Chinese traditional medicine, which we believe will bring us more surprises in the future.

Mitochondria are in a dynamic and highly mobile state, and mitochondrial quality control (MQC) is an effective way for mitochondria to maintain their dynamic homeostasis, which mainly includes mitochondrial dynamics, mitochondrial biogenesis, mitochondrial autophagy and other processes. Mitochondrial dynamics includes mitochondrial fusion and fission which redistributes mitochondrial components, prevents defective mitochondria from continuing to fuse and helps restore damaged mitochondrial membrane activity. Optic atrophy1 (OPA1) (Westermann, 2010; Luo et al., 2015). Astragaloside II (AS-II) (Su et al., 2021) has been found to improve mitochondrial dynamics by upregulating Mitofusin 2 (MFN2) expression and decreasing Fission 1 (FIS1) expression in DKD rats studied in vivo. MFN2 is a protein involved in mitochondrial membrane fusion. FIS1 is located in the mitochondrial membrane and regulates mitochondrial division.

Mitochondrial fission can separate damaged mitochondria prior to mitochondrial autophagy (Yang et al., 2017). Its related proteins include mitochondrial dynamin-related proteins (DRPs) and mitochondrial fission family, etc. DRP1 is a large GTPase, that is, translocated from the cytoplasmic matrix to the OMM, forming a ring-like oligomeric structure around the fragmented membrane. After mitochondrial fission, DRP1 returns from the OMM to the cytoplasmic matrix. Decreasing DRP1 expression enhances mitochondrial fusion and forms enlarged mitochondria, while increasing DRP1 expression results in mitochondrial fragmentation. FIS1 phosphorylated on OMM binds to DRP1 and co-regulates mitochondrial fission. In addition, FIS1 can eventually trigger apoptosis through the induction of Cyto c (Lee et al., 2004). A study Liu et al. (2017) showed that Astragaloside IV (AS-IV) significantly improved the down-regulated expression of DRP-1, FIS-1 in a db/db mouse model. In vitro and in vivo experiments have demonstrated that BBR can phosphorylate DRP1 and use mitochondrial fission to eliminate excess mtROS (Kim and Lee, 2021). BBR may improve mitochondrial dynamics by blocking Drp1 expression and translocation to mitochondria in lentivirus-infected foot cells expressing DRP1 (Qin et al., 2019). PD can improve mitochondrial function and morphological changes through ROS/DRP1/mitochondrial fission, and this pathway is expected to be a new therapeutic target (Ni et al., 2017). Melatonin improves kidney mitochondrial dynamics by inhibiting fission and promoting fusion, as well as improving mitochondrial physiology, thus enhancing kidney function in diabetic obese rats. Promote fusion protein MFN2 and OPA1 expression, promote fusion, and restore fission protein DRP1 to normal. Increase compound IV activity (Agil et al., 2020).

Mitochondrial Pathway Autophagy is a selective autophagy process in which damaged and senescent mitochondria are specifically identified and cleared under stressful conditions to maintain internal environmental stability (Green and Van Houten, 2011; Novak, 2012). PTEN induced putative kinase 1 (PINK1) is a parkin-recruitment factor from the cytoplasmic to damage mitochondria in a membrane potential-dependent manner for mitochondrial degradation (Matsuda et al., 2010). PINK/Parkin/P62 is a classical pathway for mitochondrial autophagy, and PINK1 is located upstream of Parkin. When the membrane potential decreases, Parkin is activated and displaced, cytosolic p62 translocates to the mitochondria and binds to the polymerized ubiquitin-binning domain, which then binds to LC3-interacting region (LIR) to facilitate autophagy completion (Gottlieb et al., 2021). The study found that AS II (Liu et al., 2017) and Jujuboside A (Zhong et al., 2022) downregulated PINK1/Parkin-mediated mitochondrial autophagy to improve mitochondrial dysfunction. Sestrin2 (Sesn2) is a highly conserved protein that can be derived under a variable of stress conditions, which has been shown to regulate AMPK activation to maintain mitochondrial functional integrity and reduce ROS production. In vitro and in vivo studies demonstrated that Icariin (ICA) was associated with increased Sesn2-mediated mitochondrial autophagy and reduced NLRP3 inflammatory small-body activation in the Sesn2/PINK1/Parkin signaling pathway (Ding et al., 2022).

In addition, there also have other Parkin independent pathways and mitochondrial autophagy mediated by receptors such as NIX/BNIP3L, BNIP3, and FUNDC1. But there are no studies as extensive as the Parkin-dependent pathway described above.

Mitochondrial biogenesis is a continuous process of producing new mitochondria; PGC-1α is the primary upstream regulator of mitochondrial biogenesis, and AMPK and SIRT1 is its upstream regulator. Because PGC-1α is almost ubiquitous, targeting its upstream regulatory receptors is often considered an important method for restoring mitochondrial function (Ruozhi et al., 2021). Grape seed proanthocyanidins extract (GSPE) restores mtDNA content and improves mitochondrial dysfunction by activating the AMPK-SIRT1-PGC-1α signaling pathway (Bao et al., 2014). RESV (Zhang T. et al., 2019) and Salidroside (Xue et al., 2019) enhance the activity of the SIRT1 and PGC-1α pathway, promote mitochondrial biosynthesis, inhibit mitochondrial OS, and improve kidney damage. PGC-1α promotes mitochondrial transcription factors such as nuclear response factor 1/2 (NRF1/2) and transcription factor a mitochondrial (TFAM). RESV (Kitada et al., 2011) and BBR (Qin et al., 2019) reversed the low expression of PGC-1α and the downstream factors described above, increasing mtDNA content and improving mitochondrial biogenesis. Syringic Acid (SYR) (Rashedinia et al., 2020; Rashedinia et al., 2021) reverses low mRNA expression of PGC-1α and NRF-1 in diabetic rats, increases mtDNA/nDNA ratio, decreases antioxidant enzyme activity such as CAT, and regulates mitochondrial biosynthesis and oxidative stress to mitigate mitochondrial damage. RESV may enhance mitochondrial biogenesis by reducing OS (Kitada et al., 2011). SIRT3, a member of the SIRT family, is primarily present in the linear granule matrix and also regulates the indirect mitochondrial functions of PGC-1α, Complex I, II, and SOD2 (Morigi et al., 2018). Honokiol restored Sirt3 expression in BTBR ob/ob mice, inhibited OS through SIRT3, SOD2, restored PGC-1α levels, and improved mitochondrial morphology and function (Locatelli et al., 2020).

Mitochondria are the only organelles with unique genomes (mtDNA) (Gottlieb et al., 2021). Mitochondria include nuclear DNA (nDNA) and mtDNA. Compared to nDNA, mtDNA lacks an effective DNA damage repair system and histone protection, making mtDNA more susceptible and difficult to repair (Luo et al., 2015). MtDNA is exposed to respiratory chains and mitochondrial membranes, making it more sensitive to OS, and mtDNA and oxidative stress interact: abnormal increases in ROS lead to mtDNA breaks, which in turn induces an inflammatory response that increases ROS and further exacerbates damage if mtDNA oxidizes. Because abnormal mitochondrial function continues to affect mtDNA integrity; Therefore, we have to consider how much mtDNA is involved in almost any manifestation of mitochondrial abnormalities. The previously mentioned monomer components of RESV, SYR, GSPE, and Salidroside all reverse damage caused by mtDNA acting in concert with other mechanisms of mitochondrial dysfunction.

When ETC synthesizes ATP, a large number of protons are produced, and the mitochondrial membrane potential (MMP) caused by this concentration difference also provides the power for mitochondrial uptake of cytosolic Ca²⁺, a selective pathway for mitochondrial matrix uptake called mitochondrial Ca²⁺ uniporter (MCU). Overexpression of MCU led to increased mitochondrial Ca²⁺ and decreased cytoplasmic Ca²⁺, leading to decreased MMP and increased abnormal openness of mPTP. In fact, at least three dehydrogenases in the TCA cycle are regulated by the mitochondrial substrate Ca²⁺, which mediates oxidative phosphorylation. Due to Ca2⁺-ATP enzyme regulation, moderate calcium in the mitochondria promotes ATP synthesis, while calcium overload leads to mPTP opening, decreased membrane potential, and apoptotic protein spillovers, so regulating calcium balance plays an important role in MQC. Ca²⁺ throughput chemiluminescence (CHL) assay confirmed increased oxygen consumption and ROS production in isolated mitochondria (Kanno et al., 2004).

AS-IV dose-dependent increase in Sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) activity, particularly its subtype SERCA2, evened out intracellular Ca²⁺, Ca²⁺ induces typical mitochondrial membrane permeability transition (MPT), which results in abnormal opening of mPTP, depolarization and swelling of mitochondria, and finally release Cyto c into the cytoplasmic matrix. AS-IV presumably by activating the PPAR-γ/SERCA2/Ca²⁺ pathway, inhibiting mitochondrial pathway-mediated podocytes apoptosis as well as ER-mediated apoptosis pathway (Guo et al., 2016). Canadian Transient Receptor Potential6Channel (TRPC 6) is a member of the Ca²⁺ transduction pathway in the TRPC family and is widely expressed in kidney cells, regulating podocytes by regulating calcium homeostasis. Taurine reduces mitochondrial ROS production by increasing hydrogen sulfide synthesis, increasing respiratory chain complex expression, modulating the CSE/TRPC6 axis to inhibit calcium overload, and improving mitochondrial respiratory function, ultimately reducing DN damage (Zhang et al., 2020).

Hyperglycemic state can lead to an increase in the IMM potential difference and the formation of inner membrane hyperpolarization, resulting in mitochondrial dysfunction. RESV (Yang and Zhou, 2019; Zhang B. et al., 2019), Notoginsenoside R1 (Zhang T. et al., 2019) and Luteolin (Yu et al., 2019) concentration dependent increase mitochondrial membrane potential and decrease mitochondrial damage.

OB Zhou et al. (2019) inhibits ROS production to maintain mitochondrial membrane potential stability. Mitochondria are membrane structures with high levels of unsaturated fatty acids and are vulnerable to ROS, making mPTP abnormally open, which in turn increases membrane permeability. Small molecular mass proteins continuously enter the IMM due to the hyperosmotic state of the matrix and the ion concentration gradient on both sides of the IMM disappears, ultimately leading to poor outcomes. The breakdown of MMP can occur through uncoupling of respiratory chains, and ATP synthesis is blocked, but the mechanism of this pathway needs to be further elucidated. Higher concentrations of positive ions in the mitochondrial matrix than in the cytoplasm can exacerbate swelling and even rupture mitochondria (Zhang et al., 2021). CUR relieves impaired renal mitochondrial coupling and slows MTPTP activation in rats. C3G (Wei et al., 2018) can reverse the abnormal increase of mitochondrial membrane potential, improve OS and inhibit apoptosis. Different causes of MMP decline led to increased membrane permeability, activation of apoptosis-related proteins, and apoptosis.

Apoptosis is a genetically controlled process of programmed cell death, an active suicide attempt to maintain normal tissue morphology and function. Apoptotic cells showed typical morphological changes, including follicles, nuclear consolidation and sequenced DNA fragmentation etc. Mitochondrial pathway apoptosis is a type of apoptosis, mainly characterized by a decrease in MMP and an increase in mitochondrial membrane permeability. Mitochondrial pathway apoptosis includes anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) family (Kale et al., 2018) and the pro-apoptotic protein Bax, which eventually activates pro-caspase9 and subsequently cascades into caspase-family cascades that eventually break down into apoptotic small bodies. Cyto c located outside the mitochondrial endometrium, not only mediates electron transfer of the respiratory chain, but also enters the cytoplasm in large quantities when cells are damaged and induces apoptosis (Bock and Tait, 2020).

Notoginsenoside R1 (Zhang B. et al., 2019), Polydatin (PD), BBR (Qin et al., 2019), OB (Zhou et al., 2019) C3G, Taurine (Das and Sil, 2012) and CUR (Altamimi et al., 2021) all reduce mitochondrial damage by regulating this mitochondrial apoptotic cascade pathway. Smac-DIABLO is a newly discovered mitochondrial apoptosis protein in these years. RESV reverses the release of Cyto c and Smac-DIABLO, activates caspase 3, and reduces damage caused by aberrant apoptosis. Mangiferin (MGF) inhibits TNFα-mediated apoptosis by reducing levels of released TNFα. MGF also reduced Cyto c release and reversed poly (ADP-ribose) polymerase (PARP) expression regulating apoptosis in the mitochondrial pathway (Pal et al., 2014). Phillyrin increased levels of Bcl-2 and Cyto c in mitochondria by regulating the PI3K/Akt/GSK-3β pathway, and decreased expression of cleaved caspase-3 and Bax proteins to regulate apoptosis in mitochondrial pathways (Wang et al., 2021). In HG-induced MPC-5 cells, Luteolin treatment significantly upregulated the expression of the mitochondrial apoptotic protein Bcl-2 and downregulated the expression of caspase proteins. Luteolin interfered in a similar manner to siNLRP3, inhibiting the formation of NLRP3 inflammatory small bodies and acting as an anti-apoptotic agent (Yu et al., 2019). Apoptotic protein activating-factor-1 (Apaf-1) plays an important role in mitochondrial pathway apoptosis, and Jujuboside A plays a therapeutic role by downregulating the expression of mitochondrial apoptotic proteins (Bax, Cyto c Apaf-1) (Zhong et al., 2022). In vitro and in vivo experiments, Aldose reductase (AR) is a NADPH-dependent oxidoreductase involved in the glucose metabolism polyol pathway. Recent studies (He et al., 2022) have confirmed that Ginsenoside Rb1 inhibits AR activity and its downstream factor, Recombinant Nicotinamide Adenine Dinucleotide Phosphate Oxidase 4 (NOX4), by binding to AR. Ginsenosaponin Rb1 directly or indirectly reduces NOX4 activity, inhibits ROS production, attenuates the release of Cyto c, and attenuates apoptosis, thus maintaining mitochondrial structural and functional integrity. Astragalus polysaccharide (APS) is one of the main active components of Astragalus and AMPK is a mitochondrial ATP energy receptor that can be activated when the AMP/ATP ratio increases. Subsequently, its downstream SIRT1/PGC-1α pathway was activated, and so far little research has been done on the role of APS in mitochondrial dysfunction in diabetic nephropathy. Using human proximal tubular epithelial cell line (HK-2) as a model, Xu (2020) found that APS upregulates ATP-containing and suppresses caspase-9 overexpression, confirming that APS mediates mitochondrial apoptosis through the AMPK/SIRT1/PGC-1α pathway.