Orally administered MOTS-c analogue ameliorates dextran sulfate sodium-induced colitis by inhibiting inflammation and apoptosis

Jiang, Jielin; Chang, Xin; Nie, YaoYan; Xu, Lingfei; Yang, Long; Peng, Yan; Chang, Min

doi:10.1016/j.ejphar.2022.175469

Cited by 11 publications

(6 citation statements)

References 43 publications

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“…MOTS-c was synthesized by a standard Fmoc-based solid phase synthesis methodology, as previously described. 31 All amino acids and coupling reagents were purchased from GL Biochem Ltd. (Shanghai, China). The obtained crude peptides were purified by semipreparative reversed-phase high-performance liquid chromatography (RP-HPLC).…”

Section: Methodsmentioning

confidence: 99%

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Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

Jiang

Yang

et al. 2023

ACS Chem. Neurosci.

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MOTS-c, a recently discovered mitochondrial-derived peptide, plays an important role in many physiological and pathological functions via adenosine monophosphate-activated protein kinase (AMPK) activation. Numerous studies have demonstrated that AMPK is an emerging target for the modulation of neuropathic pain. Meanwhile, microglia-activation-evoked neuroinflammation is known to contribute to the development and progression of neuropathic pain. MOTS-c is also known to inhibit microglia activation, chemokine and cytokine expression, and innate immune responses. Accordingly, in this study, we evaluated the effects of MOTS-c on neuropathic pain and investigated the putative underlying mechanisms. We found that MOTS-c levels in plasma and spinal dorsal horn were significantly lower in mice with spared nerve injury (SNI)-induced neuropathic pain than in control animals. Accordingly, MOTS-c treatment produced pronounced dose-dependent antinociceptive effects in SNI mice; however, these effects were blocked by dorsomorphin, an AMPK inhibitor, but not naloxone, a nonselective opioid receptor antagonist. Moreover, intrathecal (i.t.) injection of MOTS-c significantly enhanced AMPKα 1/2 phosphorylation in the lumbar spinal cord of SNI mice. MOTS-c also significantly inhibited proinflammatory cytokine production and microglia activation in the spinal cord. The antinociceptive effects of MOTS-c were retained even when microglia activation in the spinal cord was inhibited by minocycline pretreatment, indicating that spinal cord microglia are dispensable for the antiallodynic effects of MOTS-c. In the spinal dorsal horn, MOTS-c treatment inhibited c-Fos expression and oxidative damage mainly in neurons rather than microglia. Finally, in contrast to morphine, i.t. administration of MOTS-c resulted in limited side effects relating to antinociceptive tolerance, gastrointestinal transit inhibition, locomotor function, and motor coordination. Collectively, the present study is the first to provide evidence that MOTS-c may be a promising therapeutic target for neuropathic pain.

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Section: Methodsmentioning

confidence: 99%

“…MOTS-c was synthesized by a standard Fmoc-based solid phase synthesis methodology, as previously described . All amino acids and coupling reagents were purchased from GL Biochem Ltd. (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

Jiang

Yang

et al. 2023

ACS Chem. Neurosci.

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“… 115 A novel bioactive mitochondrial-derived peptide encoded in mitochondrial 12S rRNA, referred to as MOTS-c, has been shown to alleviate inflammatory responses, enhance anti-apoptotic capacity, upregulate p-AMPK expression, and inhibit the activation of the ERK/JNK signaling pathway, thereby exerting anti-colitis effects. 116 Cannabinoid receptor 2 (CB2R) belongs to the G-protein-coupled receptor (GPCR) family and possesses 7 transmembrane α-helices, a glycosylated extracellular N-terminus, and an intracellular carboxyl terminus. Activation of CB2R has been demonstrated to ameliorate DSS-induced colitis by inhibiting the NLRP3 inflammasome in macrophages.…”

Section: Potential Drugs Targeting Ampk-regulated Pathway In Ucmentioning

confidence: 99%

The Role of AMPK Signaling in Ulcerative Colitis

Yuan,

Wang,

Liu

et al. 2023

DDDT

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Ulcerative colitis (UC) is a chronic non-specific inflammatory bowel disease characterized by inflammation and ulcer formation of the intestinal mucosa. Due to its high recurrence rate, prolonged course, limited curative options, and significant impact on patients’ quality of life, along with a notable potential for malignant transformation, UC is designated as a refractory global health challenge by the World Health Organization (WHO). The elucidation of the pathogenesis and therapeutic strategies for UC requires further in-depth investigation. AMP-activated protein kinase (AMPK) serves as a central regulator of cellular energy metabolic homeostasis. Emerging evidence indicates that interventions involving traditional Chinese medicine (TCM) components, as well as other pharmacological measures, exert beneficial effects on the intestinal mucosal inflammation and epithelial barrier dysfunction in UC by modulating AMPK signaling, thereby influencing biological processes such as cellular autophagy, apoptosis, inflammatory responses, macrophage polarization, and NLRP3 inflammasome-mediated pyroptosis. The role of AMPK in UC is of significant importance. This manuscript provides a comprehensive overview of the mechanisms through which AMPK is involved in UC, as well as a compilation of pharmacological agents capable of activating the AMPK signaling pathway within the context of UC. The primary objective is to facilitate a deeper comprehension of the pivotal role of AMPK in UC among researchers and clinical practitioners, thereby advancing the identification of novel therapeutic targets for interventions in UC.

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“…Increased MOTS-c expression has been associated with a reduced inflammatory response in heart tissue following pressure overload 17 . MOTS-c has also exhibited anti-inflammatory properties in a mouse dextran sulfate sodium-induced colitis model 18 , possibly by suppressing the c-Jun N-terminal kinase (JNK) pathway 19 and stimulating the adenosine monophosphate-activated protein kinase pathway 20 . MOTS-c downregulation has been associated with JNK activation 21 .…”

Section: Introductionmentioning

confidence: 99%

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

Zou,

Shi,

Chang

et al. 2024

Theranostics

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Rationale: The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) promotes pathological mitochondrial fission during septic acute kidney injury. The mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c) is a mitochondria-derived peptide that exhibits anti-inflammatory properties during cardiovascular illnesses. We explored whether endotoxemia-induced myocardial microvascular injury involved DNA-PKcs and MOTS-c dysregulation. Methods: To induce endotoxemia in vivo, endothelial cell-specific DNA-PKcs- knockout mice were injected intraperitoneally with a single dose of lipopolysaccharide (10 mg/kg) and evaluated after 72 h. Results: Lipopolysaccharide exposure increased DNA-PKcs activity in cardiac microvascular endothelial cells, while pharmacological inhibition or endothelial cell-specific genetic ablation of DNA-PKcs reduced lipopolysaccharide-induced myocardial microvascular dysfunction. Proteomic analyses showed that endothelial DNA-PKcs ablation primarily altered mitochondrial protein expression. Verification assays confirmed that DNA-PKcs drastically repressed MOTS-c transcription by inducing mtDNA breaks via pathological mitochondrial fission. Inhibiting MOTS-c neutralized the endothelial protective effects of DNA-PKcs ablation, whereas MOTS-c supplementation enhanced endothelial barrier function and myocardial microvascular homeostasis under lipopolysaccharide stress. In molecular studies, MOTS-c downregulation disinhibited c-Jun N-terminal kinase (JNK), allowing JNK to phosphorylate profilin-S173. Inhibiting JNK or transfecting cells with a profilin phosphorylation-defective mutant improved endothelial barrier function by preventing F-actin depolymerization and lamellipodial degradation following lipopolysaccharide treatment. Conclusions: DNA-PKcs inactivation during endotoxemia could be a worthwhile therapeutic strategy to restore MOTS-c expression, prevent JNK-induced profilin phosphorylation, improve F-actin polymerization, and enhance lamellipodial integrity, ultimately ameliorating endothelial barrier function and reducing myocardial microvascular injury.

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Orally administered MOTS-c analogue ameliorates dextran sulfate sodium-induced colitis by inhibiting inflammation and apoptosis

Cited by 11 publications

References 43 publications

Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

Mitochondrial-Derived Peptide MOTS-c Ameliorates Spared Nerve Injury-Induced Neuropathic Pain in Mice by Inhibiting Microglia Activation and Neuronal Oxidative Damage in the Spinal Cord via the AMPK Pathway

The Role of AMPK Signaling in Ulcerative Colitis

The DNA-dependent protein kinase catalytic subunit exacerbates endotoxemia-induced myocardial microvascular injury by disrupting the MOTS-c/JNK pathway and inducing profilin-mediated lamellipodia degradation

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