Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives.

Peptides2024PMID: 38160808

View on PubMed DOI: 10.1016/j.peptides.2023.171147

Plain Language Summary

Review examining mitochondria-derived peptides—humanin, MOTS-c, and SHLPs—with a focus on their antidiabetic functions, evolutionary origins from proto-mitochondrial bacteria, and the genetic architecture of MDP-encoding regions within the mitochondrial 12S and 16S rRNA genes. Covers MOTS-c's roles in insulin sensitivity and glucose metabolism from an evolutionary perspective. Provides an evolutionary biology framework for understanding why the mitochondrial genome encodes metabolic regulatory peptides—connecting the ancient bacterial origins of mitochondria to MOTS-c's modern function as a key regulator of glucose homeostasis and insulin sensitivity.

Abstract

Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins encoded by short open-reading frames (sORF) in mitochondrial DNA (mtDNA). Currently, three types of MDPs have been identified: Humanin (HN), MOTS-c (Mitochondrial ORF within Twelve S rRNA type-c), and SHLP1-6 (small Humanin-like peptide, 1 to 6). The 12 S ribosomal RNA (MT-RNR1) gene harbors the sequence for MOTS-c, whereas HN and SHLP1-6 are encoded by the 16 S ribosomal RNA (MT-RNR2) gene. Special genetic codes are used in mtDNA as compared to nuclear DNA: (i) ATA and ATT are used as start codons in addition to the standard start codon ATG; (ii) AGA and AGG are used as stop codons instead of coding for arginine; (iii) the standard stop codon UGA is used to code for tryptophan. While HN, SHLP6, and MOTS-c are encoded by the H (heavy owing to high guanine + thymine base composition)-strand of the mtDNA, SHLP1-5 are encoded by the L (light owing to less guanine + thymine base composition)-strand. MDPs attenuate disease pathology including Type 1 diabetes (T1D), Type 2 diabetes (T2D), gestational diabetes, Alzheimer's disease (AD), cardiovascular diseases, prostate cancer, and macular degeneration. The current review will focus on the MDP regulation of T2D, T1D, and gestational diabetes along with an emphasis on the evolutionary pressures for conservation of the amino acid sequences of MDPs.

Authors

Kal, Satadeepa; Mahata, Sumana; Jati, Suborno; Mahata, Sushil K

Keywords

DiabetesHumaninMOTS-cMitochondrial peptidesand small humanin-like peptides