Abstract:Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation … Show more
“…SHLPs 1-6 comprise a class of rather recently discovered peptides, the functions of at least some of which are similar to those of HN and are currently under investigation [47,48]. As recently reported, SHLP2 has shown potent metabolic benefits through its activity on pro-opiomelanocortin neurons in the hypothalamus of the central nervous system [49]. Many other currently uncharacterized MDPs may exist [45].…”
Section: Hn and Hn-like Mitochondrial-derived Peptidesmentioning
Humanin is a 24-mer peptide first reported in the early 2000s as a new neuroprotective/cytoprotective factor rescuing neuronal cells from death induced by various Alzheimer’s disease-associated insults. Nowadays it is known that humanin belongs to the novel class of the so-called mitochondrial-derived peptides (which are encoded by mitochondrial DNA) and has been shown to exert beneficial cytoprotective effects in a series of in vitro and/or in vivo experimental models of human diseases, including not only neurodegenerative disorders but other human diseases as well (e.g., age-related macular degeneration, cardiovascular diseases, or diabetes mellitus). This review article is focused on the presentation of recent in vitro and in vivo research results associated with the neuroprotective action of humanin as well as of various, mainly synthetic, analogues of the peptide; moreover, the main mode(s)/mechanism(s) through which humanin and humanin analogues may exert in vitro and in vivo regarding neuroprotection have been reported. The prospects of humanin and humanin analogues to be further investigated in the frame of future research endeavors against neurodegenerative/neural diseases have also been briefly discussed.
“…SHLPs 1-6 comprise a class of rather recently discovered peptides, the functions of at least some of which are similar to those of HN and are currently under investigation [47,48]. As recently reported, SHLP2 has shown potent metabolic benefits through its activity on pro-opiomelanocortin neurons in the hypothalamus of the central nervous system [49]. Many other currently uncharacterized MDPs may exist [45].…”
Section: Hn and Hn-like Mitochondrial-derived Peptidesmentioning
Humanin is a 24-mer peptide first reported in the early 2000s as a new neuroprotective/cytoprotective factor rescuing neuronal cells from death induced by various Alzheimer’s disease-associated insults. Nowadays it is known that humanin belongs to the novel class of the so-called mitochondrial-derived peptides (which are encoded by mitochondrial DNA) and has been shown to exert beneficial cytoprotective effects in a series of in vitro and/or in vivo experimental models of human diseases, including not only neurodegenerative disorders but other human diseases as well (e.g., age-related macular degeneration, cardiovascular diseases, or diabetes mellitus). This review article is focused on the presentation of recent in vitro and in vivo research results associated with the neuroprotective action of humanin as well as of various, mainly synthetic, analogues of the peptide; moreover, the main mode(s)/mechanism(s) through which humanin and humanin analogues may exert in vitro and in vivo regarding neuroprotection have been reported. The prospects of humanin and humanin analogues to be further investigated in the frame of future research endeavors against neurodegenerative/neural diseases have also been briefly discussed.
“…In addition to humanin, Cobb et al identified 6 putative mitochondrial sORFs in 16S rRNA and named them small humanin-like peptides 75 . The SHLP family members exhibit distinct expression patterns and play different biological roles 77 ; for example, SHLP2 is involved in energy homeostasis 82 , SHLP3 is involved in cell survival 80 , and SHLP6 is involved in apoptosis 80 . Fig.…”
Section: Mitochondria-derived Peptides As Mitochondrial Messengersmentioning
Traditionally, mitochondria are considered sites of energy production. However, recent studies have suggested that mitochondria are signaling organelles that are involved in intracellular interactions with other organelles. Remarkably, stressed mitochondria appear to induce a beneficial response that restores mitochondrial function and cellular homeostasis. These mitochondrial stress-centered signaling pathways have been rapidly elucidated in multiple organisms. In this review, we examine current perspectives on how mitochondria communicate with the rest of the cell, highlighting mitochondria-to-nucleus (mitonuclear) communication under various stresses. Our understanding of mitochondria as signaling organelles may provide new insights into disease susceptibility and lifespan extension.
“…In addition, species such as the gray squirrel ( Sciurus carolinensis ) having size variants encoded by mitochondrial and nuclear DNA, are promising models. In vivo experimentation could focus on the metabolic outcome of the 9mer of SHLP6 administered exogenously ( Merry et al, 2020 ; Kim et al, 2023 ).…”
Section: Conclusion and Future Perspectivesmentioning
confidence: 99%
“…They promote cell proliferation [SHLP4 ( Cobb et al, 2016 )], improve cell viability, reduce cell apoptosis, and share protective effects with Humanin [SHLP2 and SHLP3 ( Cobb et al, 2016 )]. SHLP2, in addition, promotes thermogenesis in interscapular brown adipose tissue ( Kim et al, 2023 ). SHMOOSE boosts mitochondrial oxygen consumption, modifies energy signalling and metabolism in the central nervous system as well as reduces mitochondrial superoxide production ( Miller et al, 2022 ).…”
Heterothermic thermoregulation requires intricate regulation of metabolic rate and activation of pro-survival factors. Eliciting these responses and coordinating the necessary energy shifts likely involves retrograde signalling by mitochondrial-derived peptides (MDPs). Members of the group were suggested before to play a role in heterothermic physiology, a key component of hibernation and daily torpor. Here we studied the mitochondrial single-nucleotide polymorphism (SNP) m.3017C>T that resides in the evolutionarily conserved gene MT-SHLP6. The substitution occurring in several mammalian orders causes truncation of SHLP6 peptide size from twenty to nine amino acids. Public mass spectrometric (MS) data of human SHLP6 indicated a canonical size of 20 amino acids, but not the use of alternative translation initiation codons that would expand the peptide. The shorter isoform of SHLP6 was found in heterothermic rodents at higher frequency compared to homeothermic rodents (p < 0.001). In heterothermic mammals it was associated with lower minimal body temperature (Tb, p < 0.001). In the thirteen-lined ground squirrel, brown adipose tissue—a key organ required for hibernation, showed dynamic changes of the steady-state transcript level of mt-Shlp6. The level was significantly higher before hibernation and during interbout arousal and lower during torpor and after hibernation. Our finding argues to further explore the mode of action of SHLP6 size isoforms with respect to mammalian thermoregulation and possibly mitochondrial retrograde signalling.
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