Research Paper Volume 10, Issue 6 pp 1239—1256

Mitochondrial peptides modulate mitochondrial function during cellular senescence

Su-Jeong Kim 1, , Hemal H. Mehta 1, , Junxiang Wan 1, , Chisaka Kuehnemann 2, , Jingcheng Chen 3, , Ji-Fan Hu 3, , Andrew R. Hoffman 3, , Pinchas Cohen 1, ,

  • 1 Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
  • 2 Buck Institute for Research on Aging, Novato, CA 94945, USA
  • 3 Stanford University Medical School, Palo Alto Veterans Institute for Research, Palo Alto, CA 94304, USA

received: February 8, 2018 ; accepted: May 30, 2018 ; published: June 10, 2018 ;
How to Cite

Copyright: Kim et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Cellular senescence is a complex cell fate response that is thought to underlie several age-related pathologies. Despite a loss of proliferative potential, senescent cells are metabolically active and produce energy-consuming effectors, including senescence-associated secretory phenotypes (SASPs). Mitochondria play crucial roles in energy production and cellular signaling, but the key features of mitochondrial physiology and particularly of mitochondria-derived peptides (MDPs), remain underexplored in senescence responses. Here, we used primary human fibroblasts made senescent by replicative exhaustion, doxorubicin or hydrogen peroxide treatment, and examined the number of mitochondria and the levels of mitochondrial respiration, mitochondrial DNA methylation and the mitochondria-encoded peptides humanin, MOTS-c, SHLP2 and SHLP6. Senescent cells showed increased numbers of mitochondria and higher levels of mitochondrial respiration, variable changes in mitochondrial DNA methylation, and elevated levels of humanin and MOTS-c. Humanin and MOTS-c administration modestly increased mitochondrial respiration and selected components of the SASP in doxorubicin-induced senescent cells partially via JAK pathway. Targeting metabolism in senescence cells is an important strategy to reduce SASP production for eliminating the deleterious effects of senescence. These results provide insight into the role of MDPs in mitochondrial energetics and the production of SASP components by senescent cells.


AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AKT: RAC-alpha serine/threonine-protein kinase; AMPK: 5' AMP-activated protein kinase; BSA: bovine serum albumin; CPT1: carnitine palmitoyltransferase I; ECAR: extracellular acidification rate; FCCP: carbonyl cyanide 4-[trifluoromethoxy]phenylhydrazone; GLS1: glutaminase; MDPs: mitochondrial-derived peptides; mtDNA: mitochondrial DNA; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PDs: population doublings; RT: room temperature; SASPs: senescence-associated secretory phenotypes; SHLPs: small humanin-like peptides; TFA: trifluoroacetic acid; 2-DG: 2-deoxy-glucose.