Links Between Cellular Energy Metabolism and Pain Sensation.

OXPHOS is the process of coupling oxidative energy release with ATP generation. Reactive oxygen species (ROS) are generated by aberrant electron transfer during OXPHOS, while excessive ROS production results in oxidative stress and cellular damage (Figure 3 ). The inhibition of OXPHOS can lead to mitochondrial dysfunction, causing various pathological pain. 35 , 49 , 50 The activity of Complexes I, II, and III decreased in chondrocytes of osteoarthritis patients, which may lead to chondrocyte degradation and oxidative stress, aggravating the inflammatory pain responses. 51 Chemotherapy-induced neuropathic pain is associated with Complex-I- and Complex-II-mediated mitochondrial respiratory dysfunction. 52 , 53 The muscle pain caused by simvastatin treatment may be due to a considerable reduction of coenzyme Q10- and Complex I/Complex II-mediated OXPHOS in patients’ myofibers. 54 Ndufv2 (a core subunit of complex I) is correlated with single-nucleotide polymorphism rs145497186, they act together to influence the susceptibility to lumbar disk degeneration and the severity of chronic low back pain. 55 A higher proportion of Complex IV-negative fibers could be seen in patients with higher pain and more painful areas in female trapezius myalgia. 56 Neurons in C and Aδ fiber of dorsal root ganglion (DRG) exhibit reduced Complex V levels in neuropathic pain; intrathecal injection of ATP significantly attenuates these hyperalgesic responses. This symptom is likely due to the reduction of complex V leading to the decrease of ATP synthesis, thus contributing to the pain development. 57 Complex V inhibitors (eg, oligomycin) prevent hyperalgesia induced by endothelin-1. 58 Biopsy findings revealed a 45% reduction in the complex V subunit ATPase of skeletal muscle in patients with tubular aggregate myopathy. Chronic inhibition of complex V contributes to the formation of tubular aggregate, thereby promoting the onset of such disease, causing severe sarcomere disorders and muscle pain. 59 There is substantial evidence that extracellular ATP is strongly tied to peripheral and central pain signaling transduction. 60 Appropriate doses of ATP injection could produce a long-lasting analgesic effect in patients with neuropathic pain, but an overdose of ATP might elicit pain, 61 excessive intracellular ATP in the resting state evokes neuropathic pain due to increased extracellular ATP release. 62 ROS is directly or indirectly involved in the initiation and development of neuropathic pain, diabetic peripheral neuropathy, gout, endometriosis-induced pain, and intervertebral disk degeneration-induced low back pain. 63 – 67 ROS scavengers can effectively alleviate visceral pain, chemotherapy-mediated and diabetic neuropathic pain. They can also inhibit the pain signaling transduction by reducing peripheral and central oxidative stress. 68 – 70

Our narrative review was informed by a literature search (see Supplemental Digital Content 2, Supplement 2, http://links.lww.com/AA/E908 , for our search strategy) that yielded 102 articles, including 26 review and editorial articles, 16 clinical studies, and 65 laboratory studies. Five articles encompassed a combination of clinical and laboratory studies.

Cellular energy metabolism has the capacity to modulate diverse forms of pain, encompassing the signaling pathways in both nerve cells and peripheral cells (Supplemental Digital Content 1, Supplemental Figure 3, http://links.lww.com/AA/E972 ). The upregulation of HK2, PKM2, and LDH in glycolysis results in an elevation of IL-1β and IL-6, thereby playing a significant role in the initiation of migraine. 5 The myalgia induced by simvastatin therapy may be attributed to the impairment of Complex I/Complex II-mediated OXPHOS within the myofibers of patients. 54 In glycolysis, PKM2 is linked to neuropathic pain, potentially initiating the activation of extracellular regulated protein kinase (ERK) and STAT3 signaling pathways, thereby resulting in an elevation of tumor necrosis factor-α (TNF-α) and IL-1β. 27 Excessive supply of LA by activated astrocyte through an aberrant astrocyte-neuron lactate shuttle contributes to the maintenance of mechanical hyperalgesia. 31 The decline in CS activity may result in mitochondrial dysfunction, as well as the activation of astrocytes and microglia within the TCA cycle. 85 In OXPHOS, the diminishment of complex V in C and Aδ fibers of DRG neurons could potentially precipitate a decline in ATP synthesis, consequently leading to the manifestation of pain hypersensitivity responses. 57 However, an excessive intracellular accumulation of ATP can lead to the subsequent extracellular release of ATP, consequently inducing neuropathic pain via the P2X prinoreceptor 4 (P2X4) receptor. 62 The heightened mechanical sensitivity exhibited by peripheral Aδ/C fiber terminals, coupled with the augmented intensity of spinal excitatory synaptic activity in the central nervous system, contributes to the development of chemotherapy-induced neuropathic pain in an ROS-dependent manner. 69 Also, the involvement of ROS in the progression of diabetic neuropathic pain is facilitated via the thioredoxin-interacting protein/NOD-like receptor protein 3/NMDA receptor 2B (TXNIP/NLPR3/NR2B) pathway in both neurons and microglia. 70 The activation of PKM2 translocation and subsequent pSTAT3 and high mobility group box-1 protein (HMGB1) signaling were observed to lead to the sustained activation of astrocytes. 28 LA plays a significant role in the migration and activation of immune cells, which subsequently undergo proliferation and release ILs and inflammatory mediators. 34 PDK2/4 that inhibit PDH activity promote peripheral LA surge and central sensitization, leading to the increase of TNF-α, IL-1β, IL-6, and pERK, indicating that PDK-PDH-LA axis as an essential link between metabolism and inflammation-driven pain hypersensitivities. 36 , 37 IFN-β induces lower IDH activity and controls the cellular α-ketoglutarate/succinate ratio in macrophages, consequently leading to the suppression of Jumonji domain-containing protein 3/interferon regulatory factor 4 (JMJD3-IRF4) dependent responses, which can be reversed by α-ketoglutarate supplement. 41 The aggregation of succinate resulting from reduced SDH activity triggers the activation of the succinate/SUCNR1(succinate receptor 1)-HIF-1α/NLPR3 pathway. 46 The diminished activity of Complex I, II, and III affects several pathways in osteoarthritis, including mitochondrial DNA mutation-induced mitochondrial dysfunction, increased inflammatory mediators, and oxidative stress. 51

Dexmedetomidine possesses analgesic and sedative properties, which can inhibit glucose sensor GLUT1 and HK2 and PFK1, thus significantly reducing the levels of glucose, pyruvate, and LA, eventually regulating neuropathic pain. 86 SGLT1 inhibitors may serve as one of the therapeutic agents for the treatment of gout with or without comorbid diabetes. 11 SGLT2 inhibitors may improve diabetic neuropathy by increasing the conduction velocity of sensory and motor nerves and reducing sympathetic nerve activity, which may help alleviate pain. 12 Clinical and Potential Preclinical Analgesics Acting on Glycolysis Abbreviations: ANLS, astrocyte-neuron lactate shuttle; 4-CIN, α-cyano-4-hydroxycinnamate; DRG, dorsal root ganglion; ERK, regulated protein kinase; GLUT1, glucose transporter 1; HK2, hexokinase 2; LDH, lactate dehydrogenase; NSC34, neuroblastoma x spinal cord cells; PC12, pheochromocytoma cells; PFK, phosphofurctokinase; PGAM1, phosphoglycerate mutase 1; PGK1, phosphoglycerate kinase 1; PKM2, pyruvate kinase M2; PKM2-IN-1, a specific inhibitor of PKM2; ROS, reactive oxygen species; SGLT1, sodium-glucose-linked cotransporter 1; siRNA, small interfering ribonucleic acid; STAT3, signal transducer and activator of transcription 3; Tat-PGAM1, Tat-phosphoglycerate mutase 1. Clinical and Potential Preclinical Analgesics Acting on Mitochondrial TCA Cycle Abbreviations: CS, citrate synthase; DRG, dorsal root ganglion; HIF-1α, hypoxia-inducible factor 1α; IL-10, interleukin-10; i.p., intraperitoneal; i.th., intrathecal; LDH, lactate dehydrogenase; MHC IIa, myosin heavy chains Ⅱa; NLPR3, NOD-like receptor protein 3; NRF-2, nuclear respiratory factor-2; PDH, pyruvate dehydrogenase; PDK, pyruvate dehydrogenase kinase; PGE2, prostaglandin E2; SDH, succinic dehydrogenase; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; SUCNR1, succinate receptor 1; TCA, tricarboxylic acid; TRPV1, transient receptor potential vanilloid 1. PGK1 activator protects the neuronal cells by inhibiting the inflammatory cascade and neuronal apoptosis. The candidate drugs such as 7979989, Z112553128, and terazosin analogs may become potential targets for treating neurological diseases and pain. 87 , 88 Using Tat-PGAM1 (fusion protein) that can easily cross the BBB and reach target cells can inhibit spinal microglial activation and release proinflammation 13 (Table 1 ). Systemic administration of celecoxib reduces prostaglandin E2 (PGE2) induced acute inflammatory pain by inhibiting PDH activity. 89 The treatment with sesame oil and crocin reduces pain response in mice with osteoarthritis, accompanied by increased CS activity and decreased IL-6 level. 90 , 91 The antinociceptive mechanism of traditional Chinese medicine paeoniflorin is related to the succinate-mediated SUCNR1/HIF-α/NLPR3 signaling pathway. 46 Oral or topical injection of PDK inhibitor dichloroacetate effectively decreases inflammatory pain in rodent models. 36 , 92 Itaconate is synthesized from cis-aconitate of the TCA cycle in macrophages, it exerts an analgesic effect in neuropathic pain by activating STAT3/β-endorphin signaling and increasing the levels of anti-inflammatory cytokine IL-10 93 (Table 2 ). Carbamazepine is the first-line class drug for trigeminal neuralgia treatment, combined coenzyme Q10 (CoQ10) therapy reduces mitochondrial oxidative stress and alleviates pain more effectively. 94 The pain control mechanism of local anesthetic ropivacaine is associated with the inhibition of Complex I and Complex II activity, subsequently leading to energy depletion and oxidative stress. 95 Propofol can inhibit complex I, complex II, and cytochrome C, and suppress the mitochondrial function as an uncoupling agent in OXPHOS. 96 The action of isoflurane includes the direct inhibition of complex I, restriction of excitatory vesicle endocytosis and exocytosis, and the reduction of presynaptic recycling and ATP production. 97 , 98 ATP can be used as the treatment of neuropathic pain, 57 , 61 but overdose ATP is a contributing factor of pain. 62 Clinical and Potential Preclinical Analgesics/Anesthetic Acting on OXPHOS Pathway Abbreviations: Akt, serine/threonine kinase; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; CaMK2α-MCU, Ca 2 + /calmodulin dependent protein kinase 2α-mitochondrial Ca 2 + uniporter; CeA, central nuclei; CoQ10, coenzyme Q10; EC 50 , 50% effective concentrations; HepG2, hepatocyte carcinoma cell line; i.d., intradermal; i.p., intraperitoneal; i.pl., intraplantar; i.th., intrathecal; iv, intravenous; MOTS-c, mitochondrial-derived peptide; mTOR, mammalian target of rapamycin; NV241, a cell-permeable succinate produrg (a mitochondrially targeted alternative energy substrate); OXPHOS, oxidative phosphorylation; P66hsc, an isoform of the shcA adaptor protein family; PBMCs, peripheral blood mononuclear cells; PBN, N-tert-butyl-α-phenylnitrone; ROS, reactive oxygen species; siRNA, small interfering ribonucleic acid; TXNIP/NLRP3/NR2B, thioredoxin-interacting protein/NOD-like receptor protein 3/N-methyl-D-aspartic acid receptor 2B pathway. The toxicity caused by an overdose of some analgesics is also related to OXPHOS. Overdose of acetaminophen leads to mitochondrial toxicity by inhibiting complex I; the use of succinate prodrug NV241 with cell permeability can alleviate its mitochondrial respiratory inhibition. 99 Bupivacaine can induce mitochondrial stress and neuronal apoptosis, and affected by the Ca 2 + /calmodulin dependent protein kinase 2α-mitochondrial Ca 2 + uniporter (CaMK2α-MCU) signaling pathway, the inhibition of CaMK2α-MCU can effectively reduce the neuronal toxicity of bupivacaine. 100 High expression of p66shc was found in the cartilage of patients with osteoarthritis. The local injection of p66shc siRNA nanoparticles into the knee joint alleviates arthritis pain by improving mitochondrial dysfunction and inhibiting ROS production. 101 Mitochondrial-derived peptide MOTS-c produces analgesic effects, which have been found to correlate with the inhibition of AMPK-induced microglia activation and reduction of neuronal oxidative stress. 102 The analgesic effect of ROS scavenger tempol and PBN is linked to the central and peripheral conduction systems of pain. The mechanism includes the inhibition of excitability and excitatory synaptic transmission in central amygdala neurons, the mechanical sensitivity of Aδ and C fiber terminals, and the block of the TXNIP/NLRP3/NR2B signaling pathway 68 – 70 (Table 3 ).

Normal cells primarily rely on mitochondrial OXPHOS, providing energy to cells, while most tumor cells are dependent on aerobic glycolysis, a phenomenon known as “Warburg effect.” This metabolic shift is driven by various stimulation and energy requirements. Neuroinflammation stimulates cellular metabolic reprogramming, enhancing the glycolysis by promoting glucose uptake, increasing PFK-1 activity and LA levels, thus eliciting an effect similar to the “Warburg effect.” 18 Glycolysis enhancement in neuropathic pain exhibits the accumulation of LA, succinate, citric acid, and α-ketoglutarate. They promote microglia to further release the proinflammatory cytokines. Also, astrocytes can increase glucose uptake and induce anaerobic glycolysis. The increased LA can shuttle from astrocytes to neurons, affecting synaptic remodeling and central sensitization. 71 This abnormal “astrocyte-to-neuron lactate shuttle” is believed to be the driving force behind the altered lactate metabolism, where astrocytes, supply activated neurons with energy via LA, 72 thereby mediating pain signal transduction. PKM2 is directly related to pain and metabolic reprogramming, 73 and hypoxia-inducible factor 1α (HIF-1α) is also an essential factor for regulating metabolic reprogramming and inflammatory response. 74 PKM2 activation inhibits the direct binding of PKM2/HIF-1α complex and IL-1β promoter under inflammatory stimuli, then decreases the expression of HIF-1α and IL-1β, thus restricting the glycolysis. The regulation of HIF-1α and IL-1β via PKM2 precisely determines factors that mediate the “Warburg effect.” 75 Isoschaftoside suppresses the inflammatory process in microglia by decreasing the expression of HIF-1α, HK2, PFKFB3 levels, and mitigating HIF-1α-mediated metabolic reprogramming. 76 Increased expression of PDKs and the subsequent inhibition of PDH activity lean more toward the transition of energy metabolism from OXPHOS to glycolysis and then increase the production of LA, which in turn regulates neuronal excitability and glial activation 36 , 77 The deficiency of PDK2/4 downregulates the levels of LA in DRG and inhibits microglia activation, thus preventing diabetic neuropathic pain. 78 The elevation of PDK3 is the typical characteristic of osteoarthritis patients with invasive and proliferative fibroblast-like synoviocytes. PDK inhibition transits cellular energy metabolism from glycolysis to OXPHOS, then suppresses the cytokines release and cell proliferation phenotype, leading to metabolic reprogramming without affecting the cellular steady oxidative state, which may restore the healthy phenotype of cells, thereby alleviating the progression of osteoarthritis. 79

The enhanced glycolytic response is associated with neuropathic pain, 1 diabetic neuropathy, 2 and chemotherapeutic-induce peripheral neuropathic pain. 3 , 4 2-deoxy-D-glucose (2-DG, glycolytic inhibitor) downregulates the release of inflammation-related and migraine-related factors from microglia activation, thus inhibiting the onset of migraine. 5 The glucose sensor localized into the membrane primarily includes facilitative glucose transporters (GLUTs) and the sodium-glucose-linked cotransporter (SGLT) family. 6 GLUT3 and SGLT3 serving as a glucose sensor can sense extracellular glucose and participate in energy metabolism regulation of neurons and glial cells through glycolysis. 7 Decreased levels of GLUT3 in the cortex are associated with neuropathic pain reduction. 8 Glycolysis of neurocytes modulate pain sensation. 2-DG is able to inhibit the glycolysis pathway. Extracellular glucose is transported to the cytosol via glucose sensors GLUT and SGLT located on the membrane. HK2, PFK1, and PKM2 are 3 key enzymes (pink) in glycolysis. HK2, GPI1, PFK1, PGK1, PGAM1, and ENO1 might regulate neuronal impulses ( dotted black arrows ) by affecting the activity of neurons and/or glial cells. PKM2, LDH, and LA are directly associated with pain ( black solid arrows ). Dexmedetomidine inhibits the activity of GLUT, HK2, and PFK, thus reducing the levels of glucose, pyruvate, and lactic acid, eventually regulating pain. 12 PGK1 activator may affect the activity of neurocytes to regulate pain signals. Tat-PGAM1 inhibits microglial activation and the release proinflammatory cytokines. 13 PKM2 inhibitors can alleviate pain response in astrocytes. Lactic acid shows a significant correlation with pain sensation.2-DG indicates 2-deoxy-D-glucose; ENO1, enolase 1; GLUT, glucose transporter; GPI1, glucose-6-phosphate isomerase 1; HK2, hexokinase 2; LA, lactic acid; LDH, lactate dehydrogenase; PFK-1, phosphofurctokinase-1; PGK1, phosphoglycerate kinase 1; PGAM1, phosphoglycerate mutase 1; PKM2, pyruvate kinase M2; SGLT, sodium-glucose-linked cotransporter; Tat-PGAM1, Tat-phosphoglycerate mutase 1. TCA cycle in mitochondria regulates the pain sensation of neurocytes. CS, IDH, α-ketoglutarate dehydrogenase are 3 key enzymes (pink) in TCA metabolism. CS, succinyl-CoA synthetase may modulate pain sensation by affecting mitochondrial function ( dotted black arrows ). Aconitase, IDH, α-ketoglutarate, succinyl-CoA synthetase possibly regulate pain signal transduction by influencing neurocyte activity ( dotted black arrows ). KGDHC can catalyze its own posttranslational modification and that of other enzymes (including IDH and fumarase). The decrease in IDH activity, and the increased activities of KGDHC, fumarase, and pyruvate dehydrogenase complex are also demonstrated after succinylation. PDKs are capable of suppressing the activity of PDH. CS indicates citrate synthase; IDH, isocitrate dehydrogenase; KGDHC, α-ketoglutarate dehydrogenase complex; PDH, pyruvate dehydrogenase; PDKs, pyruvate dehydrogenase kinase; TCA, tricarboxylic acid. OXPHOS serves as an essential pathway for pain regulation in neurocytes. The electron transfer chain is a series of complexes located on the inner mitochondrial membrane, promoting the oxidation of NADH and FADH 2 produced by glycolysis and TCA cycle, and pumping protons (H + ) out of the inner mitochondrial membrane, then utilizes a series of electron transfer reactions via OXPHOS for ATP generation. Complexes I to V are associated with multiple pain conditions. The mechanism of relevant drugs is also related to electron transfer chains and OXPHOS. ROS and ATP also closely correlate with peripheral and central pain signaling. Excessive ROS and overdose ATP could induce pain response, ROS scavenger, and suitable ATP dosage provide pain relief. ATP indicates adenosine triphosphate; FADH 2 , reduced flavin adenine dinucleotide; NADH, reduced nicotinamide adenine dinucleotide; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species; TCA, tricarboxylic acid. SGLT2 inhibitors empagliflozin is a novel pleiotropic hypoglycemic agent, which can regulate the neurotransmitters, the survival and plasticity of neurons, and exert protective effects for the function of astrocyte and microglia. 9 SGLT2 inhibitors decrease interleukin-1β (IL-1β) release by reducing microglial burden, thus protecting the function of neurocytes and improving patients’ prognosis. 10 In addition, SGLT1 inhibitors have been shown to be connected with a decrease of incident gout. 11 Although most glycolytic enzymes have not been proven to be directly associated with pain, they may affect neurocytes and play a role in pain modulation (Figure 1 ). Upregulation of hexokinase 2 (HK2), the first rate-limiting enzyme in glycolysis, has been linked to migraine attacks. 5 Glucose-6-phosphate isomerase 1 (GPI1) can protect the function of dopaminergic neurons via glycolysis. 14 The potential role of association between Gpi1 decrease and visceral pain may warrant attention and further study. 15 The most potent allosteric activator of phosphofurctokinase-1 (PFK-1) is fructose-2,6-bisphosphate, whose biosynthesis relies almost entirely on 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3). Nitric oxide-mediated inhibition of mitochondrial respiration increases PFK1 activity, redistributing glucose flow into glycolysis in astrocytes. Owing to the presence of anaphase-promoting complex/cyclosome-Cdh1, leading to degradation of PFKFB3, neurons lacking PFKFB3 cannot activate the glycolysis by increasing PFK-1 activity, thus being unable to maintain energy production. 16 , 17 The repression of microglial activation reduces glucose uptake, PFK-1 activity during neuroinflammation. 18 Aldolase A (ALDOA) might be a key target gene that is involved in synaptic vesicle-mediated substance transport and adenosine triphosphate (ATP) metabolism, thereby affecting the function of neurons. 19 Some evidence showed that the expression of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is markedly elevated in neuropathic pain models. 20 The enhancement of phosphoglycerate kinase 1 (PGK1) activity can promote the ATP generation in the brain, and reduce neuronal degradation. 21 Intraventricular injection of extracellular PGK1, which can localize to dopaminergic neurons, participates in energy supply and promotes the survival of dopaminergic neurons. 22 Moreover, PGK1 reduces microglial M1-type polarization that can promote the release of proinflammatory factors and toxic substances to exacerbate cell damage. 23 The presence of phosphoglycerate mutase 1 (PGAM1) accelerates the rate of glycolysis. Tat-PGAM1 can cross the blood-brain barrier (BBB) and cell membrane, facilitates ATP use, mitigating neuronal damage, 24 inhibiting the microglial activation and proinflammatory factors released in the ischemic spinal cord. 13 Enolase 1 (ENO1) upregulation was mainly involved in the modulation of synapses between neurons, synaptic vesicle-mediated transport, and related pathways in neurodegenerative diseases. 19 Overexpression of ENO1 alleviates neuronal spine loss and the length reduction of the dendrite, thereby protecting the neuronal function 25 and simultaneously promoting M2-type polarization of microglia. 26 The inhibition of pyruvate kinase M2 (PKM2) directly alleviates neuropathic pain. 27 Astrocytes can be activated during inflammatory pain, accompanying the increase of PKM2 and lactic acid (LA), PKM2 can translocate into the nucleus and then activate the signal transducer and activator of transcription 3 (STAT3) signaling pathway, which can be reversed by inhibiting PKM2-mediated aerobic glycolysis, thus alleviating pain response. 28 The metabolic product pyruvate produced by glycolysis enters mitochondria under aerobic conditions and then drives the TCA cycle. During hypoxia, lactate dehydrogenase (LDH) catalyzes the conversion of pyruvate to LA. A high postoperative pain level is associated with a significant rise in LDH, which can predict moderate to severe postoperative pain, thus providing an effective clinical biological indicator. 29 LA is a natural chiral molecule that includes L- and D-LA. Clinical determination of LA is mainly based on L-LA, the lactate shuttle hypothesis posits that L-LA can shuttle between neurons and astrocytes to regulate cellular energy metabolism. 30 Intrathecal administration of L-LA can induce hyperalgesia, which can be alleviated by inhibiting the L-LA delivery from activated astrocytes to neurons. LDH inhibitors can also decrease the sensitivity of the spinal cord to nociceptive stimuli, thereby reducing neuropathic pain. 31 In addition, LA could be used as a metabolic biomarker of discogenic back pain due to its obvious relevance in pain sensation. 32 Initial study has discovered that patients experiencing chronic widespread pain exhibit elevated levels of LA and glutamate in trapezius muscle and plasma. 33 In patients with rheumatoid arthritis (RA), intercellular and articular cavities of inflammatory joints result in the increase of LA, migration, and activation of immune cells. This process enhances the body’s immune response, aggravating the patient’s condition. 34

The current review aims to provide an overview of anesthesia and analgesic drugs that target the cellular energy metabolism pathway, both in preclinical and clinical settings, providing novel insights and support for future advancements in clinical pain research and management.

This manuscript was handled by: Jianren Mao, MD, PhD.

The key regulators of mitochondrial biogenesis, including peroxisome proliferative activated receptor-γ coactivator-1α (PGC-1α), sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK), are involved in pain sensation (Supplemental Digital Content 1, Supplemental Figure 2, http://links.lww.com/AA/E972 ). The nociceptive pain (such as musculoskeletal pain, and headaches) involves signaling pathways that are activated by AMPK and regulate mitochondrial biogenesis via PGC-1α-SIRT3 positive feedback loop. 50 , 80 , 81 In neuropathic pain, PGC-1α serves as a principal regulator and potential therapeutic target, which is regulated by SIRT1 and AMPK, then operating via the nuclear respiratory factor-1 and -2 (Nrf-1/2) and mitochondrial transcription factor A (TFAM) axis. 82 In osteoarthritis, mitochondrial biogenetic processes are regulated by PGC-1α, along with Nrf-1/2, which subsequently increase the level of TFAM and nuclear-encoded mitochondrial proteins (NEMPs). Pathways such as AMPK/SIRT1/PGC-1α have emerged as promising targets for alleviating osteoarthritis cartilage lesions. 83 In RA, PGC-1α mRNA is controlled by both methyltransferase-like 3 (METTL3) and YTHN-6-methyladenosine RNA binding protein 2 (YTHDF2), which inhibit mitochondrial biogenesis and mediate synovial inflammation via PGC-1α/Nrf1/TFAM pathway. Simultaneously, mitochondrial neogenesis can be directly stimulated by activating the AMPK/SIRT1/PGC-1α pathway. 84

The authors are grateful for the help of colleagues at the Department of Anesthesiology, Shenzhen Second People’s Hospital.