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Research Paper|Volume 8, Issue 4|pp 796—809

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

Laura J. Cobb1,5, Changhan Lee2, Jialin Xiao2, Kelvin Yen2, Richard G. Wong2, Hiromi K. Nakamura1, Hemal H. Mehta2, Qinglei Gao1, Carmel Ashur1, Derek M. Huffman4, Junxiang Wan2, Radhika Muzumdar3, Nir Barzilai4, Pinchas Cohen2
  • 1Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
  • 2Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
  • 3Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
  • 4Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • 5Current address: LCS Executive Consulting, North Hollywood, CA 91607, USA
Received: August 28, 2015Accepted: April 2, 2016Published: April 10, 2016
https://doi.org/10.18632/aging.100943

Copyright: © 2016 Cobb et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.