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

Laura J. Cobb, Changhan Lee, Jialin Xiao, Kelvin Yen, Richard G. Wong, Hiromi K. Nakamura, Hemal H. Mehta, Qinglei Gao, Carmel Ashur, Derek M. Huffman, Junxiang Wan, Radhika Muzumdar, Nir Barzilai, Pinchas Cohen

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)796-809
Number of pages14
JournalAging
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Insulin Resistance
Apoptosis
Peptides
Mitochondrial DNA
Mitochondria
16S Ribosomal RNA
Glucose
Glucose Clamp Technique
Gene Expression Profiling
Adipocytes
Computer Simulation
Action Potentials
humanin
Reactive Oxygen Species
Cell Survival
Insulin
Messenger RNA
Survival
Liver

Keywords

  • aging
  • humanin
  • mitochondria
  • SHLP
  • small ORFs

ASJC Scopus subject areas

  • Aging
  • Cell Biology

Cite this

Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. / Cobb, Laura J.; Lee, Changhan; Xiao, Jialin; Yen, Kelvin; Wong, Richard G.; Nakamura, Hiromi K.; Mehta, Hemal H.; Gao, Qinglei; Ashur, Carmel; Huffman, Derek M.; Wan, Junxiang; Muzumdar, Radhika; Barzilai, Nir; Cohen, Pinchas.

In: Aging, Vol. 8, No. 4, 01.04.2016, p. 796-809.

Research output: Contribution to journalArticle

Cobb, LJ, Lee, C, Xiao, J, Yen, K, Wong, RG, Nakamura, HK, Mehta, HH, Gao, Q, Ashur, C, Huffman, DM, Wan, J, Muzumdar, R, Barzilai, N & Cohen, P 2016, 'Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers', Aging, vol. 8, no. 4, pp. 796-809. https://doi.org/10.18632/aging.100943
Cobb, Laura J. ; Lee, Changhan ; Xiao, Jialin ; Yen, Kelvin ; Wong, Richard G. ; Nakamura, Hiromi K. ; Mehta, Hemal H. ; Gao, Qinglei ; Ashur, Carmel ; Huffman, Derek M. ; Wan, Junxiang ; Muzumdar, Radhika ; Barzilai, Nir ; Cohen, Pinchas. / Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. In: Aging. 2016 ; Vol. 8, No. 4. pp. 796-809.
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