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Subcellular Fractionation for ERK Activation Upon Mitochondrial-derived Peptide Treatment
Published on: September 25, 2017
Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity,
Laura J Cobb1,2, Changhan Lee3, Jialin Xiao3
1Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
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.
Insights
Mitochondria produce small peptides, including SHLP2 and SHLP3, that protect cells, enhance metabolism, and improve insulin sensitivity, offering new insights into aging and disease.
Area of Science:
- Mitochondrial biology
- Molecular genetics
- Aging research
Background:
- Mitochondria are crucial in aging and age-related diseases.
- Mitochondrial DNA (mtDNA) encodes small mRNAs, including Humanin (HN).
- HN is a known neuroprotective peptide.
Purpose of the Study:
- To identify and characterize novel mitochondrial-derived peptides.
- To investigate the functional roles of small humanin-like peptides (SHLPs).
- To explore the potential mechanisms of action for SHLPs in cellular processes and metabolism.
Main Methods:
- In silico analysis to identify SHLPs from mtDNA.
- In vitro studies assessing cell viability, apoptosis, reactive oxygen species (ROS) generation, and mitochondrial metabolism.
- 3T3-L1 pre-adipocyte differentiation assays.
- Systemic hyperinsulinemic-euglycemic clamp studies in vivo.
Main Results:
- Six novel SHLPs were identified alongside Humanin.
- SHLP2 and SHLP3 demonstrated significant protective effects, reducing apoptosis and ROS, and improving mitochondrial metabolism.
- SHLP2 and SHLP3 promoted 3T3-L1 pre-adipocyte differentiation.
- Intracerebral SHLP2 infusion improved glucose uptake and suppressed hepatic glucose production, acting as an insulin sensitizer.
- Circulating SHLP2 levels decreased with age, similar to HN.
Conclusions:
- Mitochondria synthesize peptides that play critical roles in cellular metabolism and survival.
- SHLP2 and SHLP3 are novel mitochondrial peptides with significant biological functions relevant to aging and metabolic health.
- These findings offer new insights into mitochondrial biology and its implications for human health and disease.
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