Mitochondrial-derived peptides: Antidiabetic functions and evolutionary perspectives.

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.

Wnt5A-Mediated Actin Organization Regulates Host Response to Bacterial Pathogens and Non-Pathogens.

Wnt5A signaling facilitates the killing of several bacterial pathogens, but not the non-pathogen E. coli DH5α. The basis of such pathogen vs. non-pathogen distinction is unclear. Accordingly, we analyzed the influence of Wnt5A signaling on pathogenic E. coli K1 in relation to non-pathogenic E. coli K12-MG1655 and E. coli DH5α eliminating interspecies variability from our study. Whereas cell internalized E. coli K1 disrupted cytoskeletal actin organization and multiplied during Wnt5A depletion, rWnt5A mediated activation revived cytoskeletal actin assembly facilitating K1 eradication. Cell internalized E. coli K12-MG1655 and E. coli DH5α, which did not perturb actin assembly appreciably, remained unaffected by rWnt5A treatment. Phagosomes prepared separately from Wnt5A conditioned medium treated K1 and K12-MG1655 infected macrophages revealed differences in the relative levels of actin and actin network promoting proteins, upholding that the Wnt5A-Actin axis operates differently for internalized pathogen and non-pathogen. Interestingly, exposure of rWnt5A treated K1 and K12-MG1655/DH5α infected macrophages to actin assembly inhibitors reversed the scenario, blocking killing of K1, yet promoting killing of both K12-MG1655 and DH5α. Taken together, our study illustrates that the state of activation of the Wnt5A/Actin axis in the context of the incumbent bacteria is crucial for directing host response to infection.

Wnt5A Signaling Promotes Defense Against Bacterial Pathogens by Activating a Host Autophagy Circuit.

Bacterial pathogens are associated with severe infections (e.g., sepsis) and exacerbation of debilitating conditions such as chronic obstructive pulmonary disease (COPD). The interactions of bacterial pathogens with macrophages, a key component of innate immunity and host defense, are not clearly understood and continue to be intensively studied. Having previously demonstrated a role of Wnt5A signaling in phagocytosis, we proceeded to decipher the connection of Wnt5A signaling with infection by pathogenic bacteria, namely Pseudomonas aeruginosa (PA) and Streptococcus pneumoniae (SP), which are related with the progression of COPD and sepsis. We found that during the initial hours of infection with PA and SP, there is decrease in the steady state levels of the Wnt5A protein in macrophages. Suppression of Wnt5A signaling, moreover, impairs macrophage clearance of the bacterial infection both in vitro and in vivo. Activation of Wnt5A signaling, on the other hand, enhances clearance of the infection. Macrophage-mediated containment of bacterial infection in our study is dependant on Wnt5A-induced Rac1/Disheveled activation and cytochalasin D inhibitable actin assembly, which is associated with ULK1 kinase activity and LC3BII accumulation. Our experimental findings are consistent with Wnt5A signaling-dependent induction of autophagic killing (xenophagy) of PA and SP, as further substantiated by transmission electron microscopy. Overall, our study unveils the prevalence of a Wnt5A-Rac1-Disheveled-mediated actin-associated autophagy circuit as an important component of innate immunity in host macrophages that may turn out crucial for restricting infection by leading bacterial pathogens.