ID MOTSC_HUMAN Reviewed; 16 AA. AC A0A0C5B5G6; DT 13-APR-2016, integrated into UniProtKB/Swiss-Prot. DT 29-APR-2015, sequence version 1. DT 24-JAN-2024, entry version 26. DE RecName: Full=Mitochondrial-derived peptide MOTS-c {ECO:0000303|PubMed:25738459}; DE AltName: Full=Mitochondrial open reading frame of the 12S rRNA-c {ECO:0000303|PubMed:25738459}; GN Name=MT-RNR1 {ECO:0000312|HGNC:HGNC:7470}; OS Homo sapiens (Human). OG Mitochondrion. OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606 {ECO:0000312|EMBL:AJM13597.1}; RN [1] {ECO:0000312|EMBL:AJM13597.1} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE RP SPECIFICITY, AND MUTAGENESIS OF GLU-5 AND GLY-7. RX PubMed=25738459; DOI=10.1016/j.cmet.2015.02.009; RA Lee C., Zeng J., Drew B.G., Sallam T., Martin-Montalvo A., Wan J., RA Kim S.-J., Mehta H., Hevener A.L., de Cabo R., Cohen P.; RT "The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis RT and reduces obesity and insulin resistance."; RL Cell Metab. 21:443-454(2015). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=7219534; DOI=10.1038/290457a0; RA Anderson S., Bankier A.T., Barrell B.G., de Bruijn M.H.L., Coulson A.R., RA Drouin J., Eperon I.C., Nierlich D.P., Roe B.A., Sanger F., Schreier P.H., RA Smith A.J.H., Staden R., Young I.G.; RT "Sequence and organization of the human mitochondrial genome."; RL Nature 290:457-465(1981). RN [3] RP ROLE IN MRSA INFECTION. RX PubMed=29096170; DOI=10.1016/j.molimm.2017.10.017; RA Zhai D., Ye Z., Jiang Y., Xu C., Ruan B., Yang Y., Lei X., Xiang A., Lu H., RA Zhu Z., Yan Z., Wei D., Li Q., Wang L., Lu Z.; RT "MOTS-c peptide increases survival and decreases bacterial load in mice RT infected with MRSA."; RL Mol. Immunol. 92:151-160(2017). RN [4] RP FUNCTION, AND INDUCTION. RX PubMed=29886458; DOI=10.18632/aging.101463; RA Kim S.J., Mehta H.H., Wan J., Kuehnemann C., Chen J., Hu J.F., RA Hoffman A.R., Cohen P.; RT "Mitochondrial peptides modulate mitochondrial function during cellular RT senescence."; RL Aging (Albany NY) 10:1239-1256(2018). RN [5] RP FUNCTION, INTERACTION WITH ATF1; NFE2L1 AND NFE2L2, SUBCELLULAR LOCATION, RP AND MUTAGENESIS OF 11-TYR--LYS-14 AND 13-ARG--ARG-16. RX PubMed=29983246; DOI=10.1016/j.cmet.2018.06.008; RA Kim K.H., Son J.M., Benayoun B.A., Lee C.; RT "The Mitochondrial-Encoded Peptide MOTS-c Translocates to the Nucleus to RT Regulate Nuclear Gene Expression in Response to Metabolic Stress."; RL Cell Metab. 28:516-524(2018). RN [6] RP FUNCTION. RX PubMed=30468456; DOI=10.26355/eurrev_201811_16247; RA Hu B.T., Chen W.Z.; RT "MOTS-c improves osteoporosis by promoting osteogenic differentiation of RT bone marrow mesenchymal stem cells via TGF-beta/Smad pathway."; RL Eur. Rev. Med. Pharmacol. Sci. 22:7156-7163(2018). RN [7] RP FUNCTION. RX PubMed=31081069; DOI=10.26355/eurrev_201904_17676; RA Che N., Qiu W., Wang J.K., Sun X.X., Xu L.X., Liu R., Gu L.; RT "MOTS-c improves osteoporosis by promoting the synthesis of type I collagen RT in osteoblasts via TGF-beta/SMAD signaling pathway."; RL Eur. Rev. Med. Pharmacol. Sci. 23:3183-3189(2019). RN [8] RP ROLE IN COLD ADAPTATION. RX PubMed=31109005; DOI=10.3390/ijms20102456; RA Lu H., Tang S., Xue C., Liu Y., Wang J., Zhang W., Luo W., Chen J.; RT "Mitochondrial-Derived Peptide MOTS-c Increases Adipose Thermogenic RT Activation to Promote Cold Adaptation."; RL Int. J. Mol. Sci. 20:0-0(2019). RN [9] RP ROLE IN ADIPOSE METABOLISM. RX PubMed=30725119; DOI=10.1007/s00109-018-01738-w; RA Lu H., Wei M., Zhai Y., Li Q., Ye Z., Wang L., Luo W., Chen J., Lu Z.; RT "MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy- RT induced metabolic dysfunction."; RL J. Mol. Med. 97:473-485(2019). RN [10] RP ROLE IN OSTEOLYSIS. RX PubMed=31369811; DOI=10.1016/j.phrs.2019.104381; RA Yan Z., Zhu S., Wang H., Wang L., Du T., Ye Z., Zhai D., Zhu Z., Tian X., RA Lu Z., Cao X.; RT "MOTS-c inhibits Osteolysis in the Mouse Calvaria by affecting osteocyte- RT osteoclast crosstalk and inhibiting inflammation."; RL Pharmacol. Res. 147:104381-104381(2019). RN [11] RP TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=32182209; DOI=10.18632/aging.102944; RA D'Souza R.F., Woodhead J.S.T., Hedges C.P., Zeng N., Wan J., Kumagai H., RA Lee C., Cohen P., Cameron-Smith D., Mitchell C.J., Merry T.L.; RT "Increased expression of the mitochondrial derived peptide, MOTS-c, inb RT skeletal muscle of healthy aging men is associated with myofiber RT composition."; RL Aging (Albany NY) 12:5244-5258(2020). RN [12] RP ROLE IN VASCULAR CALCIFICATION. RX PubMed=31694019; DOI=10.1159/000503224; RA Wei M., Gan L., Liu Z., Liu L., Chang J.R., Yin D.C., Cao H.L., Su X.L., RA Smith W.W.; RT "Mitochondrial-Derived Peptide MOTS-c Attenuates Vascular Calcification and RT Secondary Myocardial Remodeling via Adenosine Monophosphate-Activated RT Protein Kinase Signaling Pathway."; RL Cardiorenal Med. 10:42-50(2020). RN [13] RP ROLE IN LUNG INJURY PROTECTION. RX PubMed=31931370; DOI=10.1016/j.intimp.2019.106174; RA Xinqiang Y., Quan C., Yuanyuan J., Hanmei X.; RT "Protective effect of MOTS-c on acute lung injury induced by RT lipopolysaccharide in mice."; RL Int. Immunopharmacol. 80:106174-106174(2020). RN [14] RP FUNCTION. RX PubMed=33554779; DOI=10.1152/ajpendo.00275.2020; RA Kumagai H., Coelho A.R., Wan J., Mehta H., Yen K., Huang A., Zempo H., RA Fuku N., Maeda S., Oliveira P.J., Cohen P., Kim S.J.; RT "MOTS-c reduces myostatin and muscle atrophy signaling."; RL Am. J. Physiol. 320:E680-E690(2021). RN [15] RP SUBCELLULAR LOCATION, INDUCTION, AND ROLE IN PHYSICAL PERFORMANCE. RX PubMed=33473109; DOI=10.1038/s41467-020-20790-0; RA Reynolds J.C., Lai R.W., Woodhead J.S.T., Joly J.H., Mitchell C.J., RA Cameron-Smith D., Lu R., Cohen P., Graham N.A., Benayoun B.A., Merry T.L., RA Lee C.; RT "MOTS-c is an exercise-induced mitochondrial-encoded regulator of age- RT dependent physical decline and muscle homeostasis."; RL Nat. Commun. 12:470-470(2021). RN [16] {ECO:0000305} RP VARIANT GLN-14. RX PubMed=26289118; DOI=10.1111/acel.12389; RA Fuku N., Pareja-Galeano H., Zempo H., Alis R., Arai Y., Lucia A., RA Hirose N.; RT "The mitochondrial-derived peptide MOTS-c: a player in exceptional RT longevity?"; RL Aging Cell 14:921-923(2015). RN [17] RP CHARACTERIZATION OF VARIANT GLN-14, FUNCTION, AND ROLE IN WEIGHT GAIN. RX PubMed=33468709; DOI=10.18632/aging.202529; RA Zempo H., Kim S.J., Fuku N., Nishida Y., Higaki Y., Wan J., Yen K., RA Miller B., Vicinanza R., Miyamoto-Mikami E., Kumagai H., Naito H., Xiao J., RA Mehta H.H., Lee C., Hara M., Patel Y.M., Setiawan V.W., Moore T.M., RA Hevener A.L., Sutoh Y., Shimizu A., Kojima K., Kinoshita K., Arai Y., RA Hirose N., Maeda S., Tanaka K., Cohen P.; RT "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived RT peptide, MOTS-c."; RL Aging (Albany NY) 13:1692-1717(2021). CC -!- FUNCTION: Regulates insulin sensitivity and metabolic homeostasis CC (PubMed:25738459, PubMed:33468709). Inhibits the folate cycle, thereby CC reducing de novo purine biosynthesis which leads to the accumulation of CC the de novo purine synthesis intermediate 5-aminoimidazole-4- CC carboxamide (AICAR) and the activation of the metabolic regulator 5'- CC AMP-activated protein kinase (AMPK) (PubMed:25738459). Protects against CC age-dependent and diet-induced insulin resistance as well as diet- CC induced obesity (PubMed:25738459). In response to metabolic stress, CC translocates to the nucleus where it binds to antioxidant response CC elements (ARE) present in the promoter regions of a number of genes and CC plays a role in regulating nuclear gene expression in an NFE2L2- CC dependent manner and increasing cellular resistance to metabolic stress CC (PubMed:29983246). Increases mitochondrial respiration and levels of CC CPT1A and cytokines IL1B, IL6, IL8, IL10 and TNF in senescent cells CC (PubMed:29886458). Increases activity of the serine/threonine protein CC kinase complex mTORC2 and reduces activity of the PTEN phosphatase, CC thus promoting phosphorylation of AKT (PubMed:33554779). This promotes CC AKT-mediated phosphorylation of transcription factor FOXO1 which CC reduces FOXO1 activity, leading to reduced levels of MSTN and promotion CC of skeletal muscle growth (PubMed:33554779). Promotes osteogenic CC differentiation of bone marrow mesenchymal stem cells via the TGFB/SMAD CC pathway (PubMed:30468456). Promotes osteoblast proliferation and CC osteoblast synthesis of type I collagens COL1A1 and COL1A2 via the CC TGFB/SMAD pathway (PubMed:31081069). {ECO:0000269|PubMed:25738459, CC ECO:0000269|PubMed:29886458, ECO:0000269|PubMed:29983246, CC ECO:0000269|PubMed:30468456, ECO:0000269|PubMed:31081069, CC ECO:0000269|PubMed:33468709, ECO:0000269|PubMed:33554779}. CC -!- SUBUNIT: Interacts with transcription factors ATF1 and NFE2L2/NRF2; the CC interactions occur in the nucleus following metabolic stress CC (PubMed:29983246). Also interacts with transcription factor NFE2L1/NRF1 CC (PubMed:29983246). {ECO:0000269|PubMed:29983246}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:25738459}. CC Mitochondrion {ECO:0000269|PubMed:29983246}. Nucleus CC {ECO:0000269|PubMed:29983246, ECO:0000269|PubMed:33473109}. CC Note=Translocates to the nucleus in response to metabolic stress in an CC AMPK-dependent manner. {ECO:0000269|PubMed:29983246}. CC -!- TISSUE SPECIFICITY: Detected in plasma (at protein level) CC (PubMed:25738459, PubMed:32182209). Also expressed in skeletal muscle CC (at protein level) (PubMed:32182209). {ECO:0000269|PubMed:25738459, CC ECO:0000269|PubMed:32182209}. CC -!- DEVELOPMENTAL STAGE: Circulating plasma levels decrease with age while CC levels in skeletal muscle increase with age (at protein level). CC {ECO:0000269|PubMed:32182209}. CC -!- INDUCTION: By exercise (PubMed:33473109). Up-regulated during cellular CC senescence (PubMed:29886458). {ECO:0000269|PubMed:29886458, CC ECO:0000269|PubMed:33473109}. CC -!- MISCELLANEOUS: Increases survival and decreases bacterial load in mice CC infected with methicillin-resistant Staphylococcus aureus (MRSA) CC (PubMed:29096170). Reduces serum levels of inflammatory cytokines such CC as TNF and IL6 and increases levels of the anti-inflammatory cytokine CC IL10 (PubMed:29096170). Enhances the phagocytic and bactericidal CC ability of macrophages and suppresses MAPK pathways while enhancing CC activation of STAT3 and AHR (PubMed:29096170). CC {ECO:0000269|PubMed:29096170}. CC -!- MISCELLANEOUS: Protects mice against lipopolysaccharide-induced acute CC lung injury (PubMed:31931370). Reduces body weight loss and pulmonary CC edema, inhibits neutrophilic tissue infiltration in lung tissue, CC reduces inflammatory cytokine levels, increases levels of anti- CC inflammatory cytokines and superoxide dismutase and down-regulates the CC expression of chemokine CXCL1/CINC1 and adhesion molecule ICAM1 in lung CC tissues (PubMed:31931370). {ECO:0000269|PubMed:31931370}. CC -!- MISCELLANEOUS: Promotes cold adaptation in mice following acute cold CC exposure (PubMed:31109005). Prevents acute cold-induced liver lipid CC deposition and increases brown fat activation and white fat browning CC upon acute cold exposure (PubMed:31109005). Also increases expression CC of thermogenic genes in vitro (PubMed:31109005). CC {ECO:0000269|PubMed:31109005}. CC -!- MISCELLANEOUS: In a mouse osteolysis model, rescues bone loss, protects CC bone mass and alleviates inflammation (PubMed:31369811). Decreases CC TNFSF11/RANKL expression, increases TNFRSF11B/OPG expression and CC reduces the number of pro-inflammatory macrophages (PubMed:31369811). CC {ECO:0000269|PubMed:31369811}. CC -!- MISCELLANEOUS: In ovarietomized mice, prevents body weight gain, CC reduces fat mass and adipocyte size, enhances brown fat function, CC decreases plasma lipid and hepatic triacylglycerol levels, and prevents CC insulin resistance. {ECO:0000269|PubMed:30725119}. CC -!- MISCELLANEOUS: Reduces weight gain in male mice fed a high-fat diet and CC enhances glucose clearance (PubMed:33468709). Does not reduce weight CC gain in females on a high-fat diet (PubMed:33468709). CC {ECO:0000269|PubMed:33468709}. CC -!- MISCELLANEOUS: Improves physical performance in both young and aging CC mice and enhances skeletal muscle adaptation to metabolic stress in CC vitro. {ECO:0000269|PubMed:33473109}. CC -!- MISCELLANEOUS: Reduces vascular calcification (VC) in a rat VC model CC (PubMed:31694019). Reverses VC-induced reduction in AMPK CC phosphorylation and decreases expression of receptors AGTR1 and EDNRB CC (PubMed:31694019). {ECO:0000269|PubMed:31694019}. CC -!- CAUTION: This peptide has been shown to be biologically active but is CC the product of a mitochondrial gene. Usage of the mitochondrial genetic CC code yields tandem start and stop codons so translation must occur in CC the cytoplasm. The mechanisms allowing the production and secretion of CC the peptide remain unclear. {ECO:0000305|PubMed:25738459}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; KP715230; AJM13597.1; -; Genomic_DNA. DR EMBL; J01415; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR AlphaFoldDB; A0A0C5B5G6; -. DR BioMuta; HGNC:7470; -. DR AGR; HGNC:7470; -. DR GeneCards; MT-RNR1; -. DR HGNC; HGNC:7470; MT-RNR1. DR MalaCards; MT-RNR1; -. DR MIM; 561000; gene. DR neXtProt; NX_A0A0C5B5G6; -. DR Orphanet; 551; MERRF. DR Orphanet; 90641; Rare mitochondrial non-syndromic sensorineural deafness. DR InParanoid; A0A0C5B5G6; -. DR ChiTaRS; RNR1; human. DR Pharos; A0A0C5B5G6; Tbio. DR PRO; PR:A0A0C5B5G6; -. DR Proteomes; UP000005640; Mitochondrion. DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB. DR GO; GO:0140297; F:DNA-binding transcription factor binding; IPI:UniProtKB. DR GO; GO:0032147; P:activation of protein kinase activity; IDA:UniProtKB. DR GO; GO:2001145; P:negative regulation of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity; IDA:UniProtKB. DR GO; GO:0001649; P:osteoblast differentiation; IDA:UniProtKB. DR GO; GO:0033687; P:osteoblast proliferation; IDA:UniProtKB. DR GO; GO:0071902; P:positive regulation of protein serine/threonine kinase activity; IDA:UniProtKB. DR GO; GO:0072522; P:purine-containing compound biosynthetic process; IDA:UniProtKB. DR GO; GO:0043610; P:regulation of carbohydrate utilization; IDA:UniProtKB. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0048630; P:skeletal muscle tissue growth; IDA:UniProtKB. PE 1: Evidence at protein level; KW DNA-binding; Mitochondrion; Nucleus; Osteogenesis; Reference proteome; KW Secreted; Transcription; Transcription regulation. FT CHAIN 1..16 FT /note="Mitochondrial-derived peptide MOTS-c" FT /evidence="ECO:0000305" FT /id="PRO_0000435952" FT VARIANT 14 FT /note="K -> Q (specific to the Northeast Asian population; FT associated with increased susceptibility of sedentary males FT to type 2 diabetes; increased plasma levels of MOTS-c FT peptide)" FT /evidence="ECO:0000269|PubMed:26289118, FT ECO:0000269|PubMed:33468709" FT /id="VAR_075685" FT MUTAGEN 5 FT /note="E->A: Lack of enhanced glycolytic response to FT glucose stimulation." FT /evidence="ECO:0000269|PubMed:25738459" FT MUTAGEN 7 FT /note="G->A: Lack of enhanced glycolytic response to FT glucose stimulation." FT /evidence="ECO:0000269|PubMed:25738459" FT MUTAGEN 11..14 FT /note="YPRK->AAAA: Abolishes nuclear localization and FT DNA-binding activity." FT /evidence="ECO:0000269|PubMed:29983246" FT MUTAGEN 13..16 FT /note="RKLR->AAAA: Does not affect nuclear localization or FT interaction with NFE2L2 but abolishes DNA-binding FT activity." FT /evidence="ECO:0000269|PubMed:29983246" SQ SEQUENCE 16 AA; 2175 MW; 361DE748426DD505 CRC64; MRWQEMGYIF YPRKLR //