title: 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.
authors.affiliation: Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.|Current address: LCS Executive Consulting, North Hollywood, CA 91607, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Cobb
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Changhan
authors.initials: C
authors.lastname: Lee
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Yen
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Wong
authors.affiliation: Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Hiromi K
authors.initials: HK
authors.lastname: Nakamura
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Hemal H
authors.initials: HH
authors.lastname: Mehta
authors.affiliation: Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of Pediatrics, Mattel Children's Hospital, and Division of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Carmel
authors.initials: C
authors.lastname: Ashur
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Derek M
authors.initials: DM
authors.lastname: Huffman
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Junxiang
authors.initials: J
authors.lastname: Wan
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D004272:DNA, Mitochondrial; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; C427211:humanin
keywords: SHLP; aging; humanin; mitochondria; small ORFs