Mitochondrial peptides modulate mitochondrial function during cellular senescence.

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

doi:10.18632/aging.101463

Abstract

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.

Highlights

Mitochondria play important roles in cellular energy production, metabolism, and cellular signaling
Immunofluorescence of mitochondria using mitochondrial outer membrane protein, mitochondrial import receptor subunit TOM20 antibodies showed that the area of TOM20 staining is more, and mitochondria appeared to be connected in the senescent cells (Fig. 1B)
To understand whether higher ATP production was due to mitochondrial respiration from more mitochondria or increased glycolysis, we measured the real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR)

Summary

Introduction

Mitochondria play important roles in cellular energy production, metabolism, and cellular signaling. These organelles have their own genomes that contain 13 mRNAs, 22 tRNAs, and 2 rRNAs to produce proteins that participate in oxidative phosphorylation. Epigenetic modification of mitochondrial DNA, including DNA methylation, is still controversial. MDPs are detected in multiple tissues and plasma, and they regulate mitochondrial bioenergetics and mitochondrial metabolism [8,9]. They play cytoprotective roles in age-related diseases, including cardiovascular diseases, diabetes and Alzheimer’s disease [10]

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