The mPTP is a non-selective channel consisting of the voltage-dependent anion channel (VDAC) located in the outer mitochondrial membrane, the adenine nucleotide translocator (ANT), and cyclophilin D (Cyp-D) complex situated in the inner mitochondrial membrane [39]. An overabundance of mtROS can induce the opening of the mPTP. CypD functions as a modulator of mPTP and is capable of concealing the inhibitory binding site for phosphate on mPTP, thus heightening mPTP’s sensitivity to ROS and Ca${}^{2+}$ [40]. Nevertheless, the administration of TRO-19622, an inhibitor of VDAC, or Mito-TEMPO, a scavenger specifically targeting mROS, can effectively alleviate the aforementioned consequences [41]. Multiple studies have provided evidence that the generation of mtROS in response to oxidative stress can be modulated via mitochondrial protective pathways, such as SIRT3. These pathways exert direct or indirect inhibitory effects on the mPTP, thereby attenuating the frequency of mPTP opening events [42].

In cases where the range of adjustment cannot be controlled, a feedback loop of negative consequences may ensue, leading to a ‘vicious cycle’. Under pathophysiological circumstances, the reversible operation of ATP synthase occurs, wherein the hydrolysis of ATP takes place, creating an electrochemical gradient that traverses the mitochondrial inner membrane. These physiological phenomena may culminate in escalated ROS levels, consequently instigating the activation of mPTP [43]. Excessive accumulation of Ca${}^{2+}$ ions and heightened levels of ROS subsequent to SCI facilitate persistent activation of mPTP. The sustained activation of mPTP results in unimpeded diffusion of molecules with a mass greater than 1.5 kilodaltons (kDa) within the mitochondria, leading to a reduction in mitochondrial membrane potential [37]. The recurrent and persistent activation of mPTP obstructs electron transport and exacerbates the impairment of the mitochondrial electron transport chain. This leads to mtROS and Ca${}^{2+}$ overload, consequently intensifying the opening of mPTP [44]. Concomitantly, subsequent to mPTP activation, the persistent elevation of mtROS can precipitate the upregulation of pro-apoptotic pathways and elicit the translocation of pro-apoptotic factors (such as caspase3) to the mitochondria, thereby potentiating mPTP aperture [45]. Pyruvate carboxylase (PYC) exerts a stabilizing effect on mPTP by suppressing oxidative stress, which in turn ameliorates motor deficits following SCI and curtails neuronal apoptosis [46]. The aforementioned investigations have demonstrated an inextricable link between mPTP activation and mitochondrial oxidative stress. The initiation of mPTP will perpetuate oxidative stress, engendering a deleterious cycle that culminates in heightened cellular impairment.

Autophagy is the process of combining damaged organelles or denatured proteins with lysosomes for self-degradation [47]. Mitophagy refers to a selective form of autophagy that functions to maintain mitochondrial homeostasis by selectively eliminating damaged or surplus mitochondria [48]. During this series of events, PTEN-induced putative kinase 1 (PINK1) perceives the depolarization of the mitochondrial membrane, leading to its accumulation on the outer membrane and the subsequent activation of Parkin. Upon activation, Parkin triggers the autophagic degradation process to achieve mitophagy. Additionally, activated Parkin can ubiquitinate other receptors located on the outer mitochondrial membrane, including NIP3-like protein X (NIX), FUNDC1, among others. These receptors can directly interact with microtubule-associated protein 1 light chain 3 (LC3), a molecule capable of sensitively detecting intracellular and extracellular signal changes and inducing the aggregation of autophagosomes [21].

The overproduction of mtROS causes a reduction in mitochondrial membrane potential (MMP). This, in turn, activates PINK1 located on the damaged outer mitochondrial membrane (OMM), engendering the initiation of ubiquitination and phosphorylation of OMM proteins, consequently promoting mitophagy [49]. Furthermore, heightened levels of ROS can trigger the initiation of mitophagy in vascular endothelial cells [50]. Mitophagy has the potential to reduce levels of ROS and may be involved in the amelioration of SCI [51]. Nonetheless, excessive mitochondrial oxidative stress can lead to an uncontrolled burst of ROS, ultimately disrupting the proper regulation of mitophagy, resulting in either an excess or deficiency of this process. This dysregulation of mitophagy is intricately associated with the onset and progression of certain pathologies. Following SCI, NIX can trigger an excessive level of mitophagy in neurons, subsequently promoting mitochondrial degeneration and neuronal cell death [52]. Research has demonstrated that betulinic acid (BA) can enhance autophagy in the context of SCI by activating the AMPK-mTOR-TFEB signaling pathway, thus promoting the induction of mitophagy and mitigating the accumulation of ROS [53]. Salidroside (Sal) has been shown to ameliorate mitochondrial dysfunction and structural abnormalities by mitigating the production of ROS. Moreover, Sal exerts its beneficial effects by augmenting the PTEN-induced PINK1-Parkin signaling pathway, which facilitates the initiation of mitophagy and enhances the clearance of impaired mitochondria [51]. These results indicate that mitochondrial oxidative stress may lead to abnormal mitophagy after SCI.

The generation of mtROS is intricately linked to the activation of pro-inflammatory cytokines [54]. The generation of ROS originating from the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase system, as well as the production of O${}^{2-}$ from the ETC within mitochondria, collectively promote the amplification of proinflammatory cytokine production [55]. mtROS exert a significant regulatory influence on the activation of the NF-$\kappa$B signaling pathway and the modulation of inflammatory vesicular signaling, consequently impacting the inflammatory response. Notably, mitochondria have been reported to play a role in the activation of NLRP3 inflammasomes through mtROS, mtDNA, and cardiolipin, although the precise contribution of mitochondria in this process remains controversial. Simultaneously, NLRP3 inflammasomes induce caspase-1-dependent damage to mitochondria, resulting in escalated mtROS production, dissipation of mitochondrial membrane potential, and compromised integrity of both the inner and outer mitochondrial membranes [56]. These findings unveil the significant involvement of mitochondrial oxidative stress in the initiation of inflammation. Activation of NLRP3 inflammasomes prompts caspase-1 activation, orchestrating the production of pro-inflammatory cytokines IL-1$\beta$ and IL-18. These cytokines, upon binding to specific intracellular receptors, potentiate the inflammatory response, ultimately culminating in organ dysfunction [57, 58]. The restitution of mitochondrial structural integrity and functional capacity impedes ROS generation, consequently mitigating the inflammatory response. Concurrently, mtROS triggers the activation of NLRP3 inflammasomes, and there is also a potential involvement of mtDNA oxidative damage in promoting a pro-inflammatory milieu [59]. Several studies have established a correlation between ETC activity and the activation of NLRP3 inflammasomes mediated by ROS. During cerebral ischemic injury, the elevated levels of succinic acid increased during ischemia, undergo oxidation. This oxidation, facilitated by reverse electron transport, stimulates ROS production within complex I, resulting in an initial surge of O${}^{2-}$ that contributes to ischemia-reperfusion injury. Consequently, the NLRP3-dependent secretion of IL-1$\beta$ is heightened, exacerbating the inflammatory response [58]. Simultaneously, it has been observed that lipopolysaccharide (LPS)-activated microglia exhibit an overproduction of chemokines, cytokines, and ROS. Within this pro-inflammatory state, the suppression of mtROS induced by LPS assumes a regulatory role in governing the synthesis of pro-inflammatory mediators by impeding the activation of MAPK and NF-$\kappa$B signaling pathways [60].

While no direct evidence of the impact of mitochondrial oxidative stress on SCI inflammation exists, research has demonstrated that the knockout of mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) can furnish neuroprotection by engaging in the oxidative stress and inflammation cascade in microglia. Moreover, PGAM5 knockout can proficiently govern mtROS and GSH levels and enhance mitochondrial dysfunction [61]. The transmission of miR-155 through exosomes is implicated in the initiation of EndoMT and the production of mtROS in bEnd.1 cells stimulated by M3-BMDMs. MtROS activates the NF-$\kappa$B signaling cascade via targeting the downstream inhibitors of cytokine signaling 6 (SOCS6), thereby restraining SOCS6-mediated p65 ubiquitination and degradation [62]. Melatonin has the capability to restrain NLRP3 inflammation activation by inducing the Nrf3/ARE pathway. This lessens the ROS and malondialdehyde (MDA) expression and boosts the superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX) activity, subsequently suppressing neuroinflammation, ameliorating mitochondrial dysfunction, and enhancing motor function recovery post-SCI [63]. This indirectly indicates that the correlation between mitochondrial oxidative damage and inflammation and requires further investigation.

mtDNA is a circular double-stranded molecule with a length of approximately 16.569, representing approximately 0.1%–1% of the total cellular DNA. The mtDNA coding region encompasses 37 genes, which consist of 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes, and 13 polypeptides [64]. The mtDNA is positioned in close proximity to the ETC. Due to its lack of nucleosomal protection and histone modification, mtDNA is vulnerable to damage, limited in its repair pathway, and prone to a high frequency of mutations, particularly under oxidative stress conditions. Thirteen peptides encoded by mtDNA play a crucial role in intracellular respiratory chain transmission and OXPHOS [65]. The mitochondrial transcription factor TFAM governs the modulation of mtDNA-encoded subunits in the ETC. Dysfunctional NRF1/2 signaling impedes the transcription of nuclear-encoded subunits of the respiratory chain complex and TFAM. The absence of TFAM packaging in the mtDNA prompts instability of the D-loop and impedes the transcription and replication of mtDNA. Consequently, diminished mtDNA transcription and replication accentuate the impairment of the respiratory chain [66]. One of the principal mechanisms by which ROS induces mtDNA damage is through oxidative modification of purine and pyrimidine bases, resulting in point mutations. ROS-mediated damage can lead to two main outcomes: (1) Structural damage, including single and double strand breaks of DNA, which are caused by direct ROS attack. The occurrence of DNA breakage following SCI was confirmed by comet assay. (2) Formation of 8-hydroxyguanine (8-OH-G). The primary products of mtDNA base damage include thymidinediol in pyrimidine nucleosides and 8-hydroxy-2${}^{\prime }$deoxyguanosine (8-oxoG) in purines. The most extensively studied oxidative base damage is 8-oxodG, which is generated by ROS attack at the C8 position of guanine. 8-oxodG serves as a reliable marker for DNA oxidative damage [67]. Prior investigations have demonstrated that the levels of 8-oxodG increase following SCI, with significant increases in 8-oxodG observed at all time points from 3 hours post-injury (hpi) to 21 days post-injury (dpi) [68]. Nonetheless, 8-oxodG may exist in various forms of nucleic acids, including cytoplasmic RNA, nuclear DNA, and mitochondrial DNA. Further investigations are warranted to elucidate the precise source of 8-oxodG. During SCI, ROS can impact ETC function and OXPHOS via mtDNA-encoded peptides, which may lead to mtDNA damage [65]. These findings indicate that mtDNA is highly vulnerable to oxidative damage induced by ROS. In a rodent model of spinal cervical spondylosis, administration of riluzole mitigated oxidative DNA damage in the spinal cord post-decompression surgery and decreased the presence of 8-oxoG DNA. Moreover, in vitro investigations demonstrated that riluzole conserved mitochondrial functionality and decreased oxidative neuronal harm [69]. Currently, limited research has explored the mechanisms underlying mtDNA repair in SCI, with existing studies primarily focusing on evaluating alterations in gene expression subsequent to SCI. Further investigations are warranted to elucidate the association between mtDNA, mitochondrial oxidative stress, and their therapeutic interventions. As our scientific inquiry progresses, numerous gaps pertaining to the understanding of mtDNA damage and repair necessitate comprehensive investigation.

In addition to the aforementioned treatments, various drugs have been found to alleviate mitochondrial oxidative stress and have neuroprotective effects on SCI. These drugs include maltol, metformin, receptor-interacting protein (RIP) inhibitors, ligustrazine, ebselen, among others [88, 89, 90, 91, 92, 93]. Erythropoietin (EPO) has been found to contribute to the recovery of reduced mitochondrial membrane potential in ferroptosis and reduce mitochondrial damage after SCI [85]. Ferrostatin-1 has been shown to inhibit mitochondrial lipid peroxidation, reduce ROS and MDA levels, and promote the expression of GSH and GPX4 in the RSL-93-induced ferroptosis model of oligodendrocytes [94]. Most antioxidants have difficulty passing through the blood-brain barrier, and the selective permeability of the mitochondrial membrane limits the targeting efficiency of many drugs on mitochondria, leading to diminished clinical effects. Thus, the efficient delivery of drugs to neuronal mitochondria while avoiding toxicity remains a challenge in SCI treatment. Moreover, apart from the aforementioned therapeutic approaches, the modulation of molecules implicated in mitochondrial oxidative stress, such as uncoupling proteins, deacetylases, and others, either individually or in combination, holds promise for reinstating neuronal mitochondrial functionality in SCI, thus affording protection to the spinal cord tissue.