MOTSC_HUMAN
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 25-MAY-2022, entry version 22.
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 GeneCards; MT-RNR1; -.
DR HGNC; HGNC:7470; MT-RNR1.
DR MalaCards; MT-RNR1; -.
DR neXtProt; NX_A0A0C5B5G6; -.
DR Orphanet; 551; MERRF.
DR Orphanet; 90641; Mitochondrial non-syndromic sensorineural deafness.
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 DNA-
FT 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
