MOTS-c is a mitochondrial-derived polypeptide with metabolic regulatory functions [1]. MOTS-c exerts anti-injury and anti-inflammatory effects by activating the AMPK pathway and inhibiting the MAP kinase-c-fos signaling pathway [2]. MOTS-c can be used in studies on stress, inflammation, metabolism, neuroprotection, and aging [3].
In vitro, MOTS-c (0-100μM; 8-24 hours) can promote the phosphorylation of AMPK (Thr 172) and Akt (Ser 473) in HEK 293 cells in a time- and dose-dependent manner [4]. Different concentrations of MOTS-c (0, 2.5, 5, 10, 20 and 40μM; 24 hours) would weaken the inhibitory effect of hypoxia treatment on the inhibition of DR4, DR5, FADD and caspase-8 in HCC cells. MOTS-c weakens the resistance of liver cancer cells to TRAIL-induced apoptosis by activating MEF2A [5].
In vivo, male C57 BL/6 mice treated with MOTS-c (5mg/kg/day; i.p.) for 7 days significantly enhanced insulin-stimulated glucose clearance rate and improved insulin sensitivity in skeletal muscle [4]. Treating mice with MOTS-c (50mg/kg; i.p.) 4 hours before formalin treatment significantly reduced the levels of pro-inflammatory cytokines in mouse serum and increased the levels of anti-inflammatory cytokines. Additionally, MOTS-c treatment significantly increased the phosphorylation level of AMPKα, inhibited the activation of spinal extracellular signal-regulated kinase (ERK), c-Jun amino-terminal kinase (JNK), and P38 in mice induced by formalin, as well as the expression of c-fos [6].
References:
[1] Benayoun B A, Lee C. MOTS‐c: a mitochondrial‐encoded regulator of the nucleus[J]. Bioessays, 2019, 41(9): 1900046.
[2] Yin X, Jing Y, Chen Q, Abbas AB, Hu J, Xu H. The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test. Eur J Pharmacol. 2020 Mar 5;870:172909.
[3] Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging[J]. Journal of Translational Medicine, 2023, 21(1): 36.
[4] Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015 Mar 3;21(3):443-54.
[5] Shen H, Nie J, Wang X, et al. MOTS-c relieves hepatocellular carcinoma resistance to TRAIL-induced apoptosis under hypoxic conditions by activating MEF2A[J]. Experimental Cell Research, 2025, 444(1): 114354.
[6] Yin X, Jing Y, Chen Q, et al. The intraperitoneal administration of MOTS-c produces antinociceptive and anti-inflammatory effects through the activation of AMPK pathway in the mouse formalin test[J]. European journal of pharmacology, 2020, 870: 172909.