ID   SHLP2_HUMAN             Reviewed;          26 AA.
AC   A0A3G1DIU6;
DT   28-JAN-2026, integrated into UniProtKB/Swiss-Prot.
DT   13-FEB-2019, sequence version 1.
DT   28-JAN-2026, entry version 4.
DE   RecName: Full=Small humanin-like peptide 2 {ECO:0000303|PubMed:27070352};
DE            Short=SHLP2 {ECO:0000303|PubMed:27070352};
GN   Name=MT-RNR2 {ECO:0000312|HGNC:HGNC:7471};
OS   Homo sapiens (Human).
OG   Mitochondrion {ECO:0000269|PubMed:27070352}.
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606 {ECO:0000312|EMBL:AMZ80337.1};
RN   [1] {ECO:0000312|EMBL:AMZ80337.1}
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RX   PubMed=27070352; DOI=10.18632/aging.100943;
RA   Cobb L.J., Lee C., Xiao J., Yen K., Wong R.G., Nakamura H.K., Mehta H.H.,
RA   Gao Q., Ashur C., Huffman D.M., Wan J., Muzumdar R., Barzilai N., Cohen P.;
RT   "Naturally occurring mitochondrial-derived peptides are age-dependent
RT   regulators of apoptosis, insulin sensitivity, and inflammatory markers.";
RL   Aging (Albany NY) 8:796-809(2016).
RN   [2] {ECO:0000305}
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] {ECO:0000305}
RP   FUNCTION.
RX   PubMed=28798389; DOI=10.1038/s41598-017-08372-5;
RA   Okada A.K., Teranishi K., Lobo F., Isas J.M., Xiao J., Yen K., Cohen P.,
RA   Langen R.;
RT   "The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like
RT   Peptide 2, Exhibit Chaperone-like Activity.";
RL   Sci. Rep. 7:7802-7802(2017).
RN   [4] {ECO:0000305}
RP   ROLE IN PROTECTION AGAINST AMD.
RX   PubMed=30310092; DOI=10.1038/s41598-018-33290-5;
RA   Nashine S., Cohen P., Nesburn A.B., Kuppermann B.D., Kenney M.C.;
RT   "Characterizing the protective effects of SHLP2, a mitochondrial-derived
RT   peptide, in macular degeneration.";
RL   Sci. Rep. 8:15175-15175(2018).
RN   [5] {ECO:0000305}
RP   FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=37468558; DOI=10.1038/s41467-023-40082-7;
RA   Kim S.K., Tran L.T., NamKoong C., Choi H.J., Chun H.J., Lee Y.H., Cheon M.,
RA   Chung C., Hwang J., Lim H.H., Shin D.M., Choi Y.H., Kim K.W.;
RT   "Mitochondria-derived peptide SHLP2 regulates energy homeostasis through
RT   the activation of hypothalamic neurons.";
RL   Nat. Commun. 14:4321-4321(2023).
RN   [6] {ECO:0000305}
RP   ERRATUM OF PUBMED:37468558.
RX   PubMed=37591868; DOI=10.1038/s41467-023-40832-7;
RA   Kim S.K., Tran L.T., NamKoong C., Choi H.J., Chun H.J., Lee Y.H., Cheon M.,
RA   Chung C., Hwang J., Lim H.H., Shin D.M., Choi Y.H., Kim K.W.;
RL   Nat. Commun. 14:4995-4995(2023).
RN   [7] {ECO:0000305}
RP   VARIANT ARG-4, CHARACTERIZATION OF VARIANT ARG-4, INTERACTION WITH
RP   MITOCHONDRIAL COMPLEX I, SUBCELLULAR LOCATION, AND IDENTIFICATION BY MASS
RP   SPECTROMETRY.
RX   PubMed=38167865; DOI=10.1038/s41380-023-02344-0;
RA   Kim S.J., Miller B., Hartel N.G., Ramirez R. II, Braniff R.G.,
RA   Leelaprachakul N., Huang A., Wang Y., Arpawong T.E., Crimmins E.M.,
RA   Wang P., Sun X., Liu C., Levy D., Yen K., Petzinger G.M., Graham N.A.,
RA   Jakowec M.W., Cohen P.;
RT   "A naturally occurring variant of SHLP2 is a protective factor in
RT   Parkinson's disease.";
RL   Mol. Psychiatry 29:505-517(2024).
RN   [8] {ECO:0000305}
RP   VARIANT ARG-4.
RX   PubMed=38940474; DOI=10.1002/mds.29892;
RG   Global Parkinson's Genetics Program;
RA   Akcimen F., van Midden V., Akerman S.C., Makarious M.B., Rothstein J.D.,
RA   Fang Z.H., Bandres-Ciga S.;
RT   "Investigating the Protective Role of the Mitochondrial 2158 T > C Variant
RT   in Parkinson's Disease.";
RL   Mov. Disord. 39:1645-1647(2024).
CC   -!- FUNCTION: Binds to and activates chemokine receptor ACKR3/CXCR7 which
CC       results in activation of proopiomelanocortin neurons in the arcuate
CC       nucleus of the hypothalamus, leading to suppression of food intake and
CC       increased energy expenditure (PubMed:37468558). Displays chaperone-like
CC       activity, inhibiting misfolding of IAPP and preventing IAPP amyloid
CC       formation (PubMed:28798389). Significantly reduces apoptosis and the
CC       generation of reactive oxygen species and improves mitochondrial
CC       metabolism in vitro (PubMed:27070352). {ECO:0000269|PubMed:27070352,
CC       ECO:0000269|PubMed:28798389, ECO:0000269|PubMed:37468558}.
CC   -!- SUBUNIT: Interacts with mitochondrial complex I.
CC       {ECO:0000269|PubMed:38167865}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:37468558}.
CC       Mitochondrion inner membrane {ECO:0000269|PubMed:38167865}.
CC   -!- MISCELLANEOUS: Encoded in the mitochondrial genome by the 16S ribosomal
CC       RNA gene MT-RNR2. {ECO:0000269|PubMed:27070352}.
CC   -!- MISCELLANEOUS: Treatment of an in vitro human transmitochondrial age-
CC       related macular degeneration (AMD) cell model with exogenous SHLP2
CC       confers cellular and mitochondrial protection (PubMed:30310092). In the
CC       AMD cell model, SHLP2 stabilizes protein levels of mitochondrial OXPHOS
CC       complex subunits, prevents loss of mitochondria, increases
CC       mitochondrial DNA copy number, prevents loss of viable cells, reduces
CC       apoptosis, and protects against amyloid-beta-induced cell death and
CC       mitochondrial damage (PubMed:30310092). {ECO:0000269|PubMed:30310092}.
CC   -!- MISCELLANEOUS: In mouse models, administration of SHLP2 results in the
CC       suppression of food intake, activation of thermogenesis, and prevention
CC       of diet-induced obesity. {ECO:0000269|PubMed:37468558}.
CC   -!- MISCELLANEOUS: Increases glucose uptake and suppresses hepatic glucose
CC       production when intracerebrally infused into rats.
CC       {ECO:0000269|PubMed:27070352}.
CC   -!- MISCELLANEOUS: Serum levels are significantly decreased in both
CC       diabetic and obese patients compared to healthy individuals.
CC       {ECO:0000269|PubMed:37468558}.
CC   -!- CAUTION: Variant Arg-4 has been reported to be associated with a
CC       decreased risk of Parkinson disease (PD) with the mutated protein
CC       showing protective activity against mitochondrial dysfunction in both
CC       in vitro and in vivo models of PD (PubMed:38167865). However, a later
CC       report disputed this finding and found no link between this variant and
CC       reduced PD risk (PubMed:38940474). {ECO:0000269|PubMed:38167865,
CC       ECO:0000269|PubMed:38940474}.
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DR   EMBL; KX067780; AMZ80337.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A3G1DIU6; -.
DR   HGNC; HGNC:7471; MT-RNR2.
DR   Proteomes; UP000005640; Mitochondrion MT.
PE   1: Evidence at protein level;
KW   Membrane; Mitochondrion; Mitochondrion inner membrane; Reference proteome;
KW   Secreted.
FT   CHAIN           1..26
FT                   /note="Small humanin-like peptide 2"
FT                   /id="PRO_0000462822"
FT   VARIANT         4
FT                   /note="K -> R (increases protein stability)"
FT                   /evidence="ECO:0000269|PubMed:38167865,
FT                   ECO:0000269|PubMed:38940474"
FT                   /id="VAR_090679"
SQ   SEQUENCE   26 AA;  3018 MW;  CBEE1C70D9C4A771 CRC64;
     MGVKFFTLST RFFPSVQRAV PLWTNS
//