Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers

Abstract

Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.

Multi-step formation, evolution, and functionalization of new cytoplasmic male sterility genes in the plant mitochondrial genomes

“…Recent studies found that in the human mitochondrial genome, besides the known genes, there are dozens of new genes for short peptides, and some have roles in regulating metabolism as well as either promoting or quelling apoptosis, suggesting that mitochondrial genomes of eukaryotes contain far more functional genes than we previously appreciated [35,36]. In plants, the large mitochondrial genomes contain more genes and putative ORFs; many of them are of unknown function.…”

MOTS-c: A novel mitochondrial-derived peptide regulating muscle and fat metabolism

“…However, emerging studies indicate that the mtDNA contains previously unknown short open reading frames (sORFs), expanding the mi-tochondrial genetic repertoire [1,4,22–24]. Notably, in various species, including humans, sORFs have been “genetic blind-spots” [23], largely due to the traditional computational cut-off of a 100 codons to avoid false-positives [25].…”

“…Recently, six additional peptides in the same region of mtDNA as humanin ( i.e. 16S rRNA) were identified using an in silico approach, and have been named small humanin-like peptides (SHLPs) 1–6 [22]. Notably, SHLPs 2 and 3 significantly reduced staurosporine-dependent apoptosis and the generation of reactive oxygen species, while increasing mi-tochondrial respiration and ATP production in vitro [22].…”

“…SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Intracerebral infusion of SHLP2 increased peripheral glucose uptake and suppressed hepatic glucose production, as determined by systemic hyperinsulinemic-euglycemic clamp studies, suggesting that it functions as an insulin sensitizer both peripherally and centrally [22]. Similar to HN, the levels of circulating SHLP2 declined with age [22].…”

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

“…Humanin is encoded from the 16S ribosomal RNA (rRNA) region of the mitochondrial genome, thus it is one of the few mitochondrial derived peptides (7). Human mitochondrial DNA contains 37 genes encoding 13 proteins, 22 transfer RNAs, and 2 rRNAs (7).…”