Mitochondrial peptides modulate mitochondrial function during cellular senescence

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.

STAT3 Regulates the Onset of Oxidant-induced Senescence in Lung Fibroblasts

“…We observed increased p21 expression, IL-6 production, cytoplasmic SA-β-Gal and pp53 following H 2 0 2 exposure, which are all recognized characteristics of senescent cells (42). Increased mitochondrial respiration was also a feature of H 2 O 2 treated fibroblasts, a characteristic previously described as being a feature of fibroblasts undergoing replicative senescence (37,38).…”

“…To further confirm senescence induction we analysed several mitochondrial characteristics as senescent fibroblasts have previously been reported to have higher levels of mitochondrial respiration (37,38). Accordingly, we tested the mitochondrial function of stress-induced senescent lung fibroblasts.…”

The Emerging Role of Senescence in Ocular Disease

“…Though an array of senescence markers has been proposed and widely used in multiple cell types, no single one can reliably identify senescent cells either in vitro or in vivo. The most widely used markers of senescence include the senescence-associated β-galactosidase (SA-β-gal) reactivity [15,20,[35][36][37][38][39], increased expression of the cyclin-dependent kinase (CDK) inhibitor p16INK4a [15,30,[36][37][38][39][40], p21 (CIP1/WAF1) [36-39, 41, 42], p53 [36,37,41,42], induction of SASP factors [14,41,[43][44][45][46][47][48][49][50], mitochondrial DNA modifications [39,[50][51][52][53][54][55][56][57], and chromatin modifications [37,47,58,59] ( Figure 1). The limitation is that even a combination of multiple markers does not truly represent senescence but could also describe long-term cell arrest.…”

“…Repeated exposure stress can also induce ROS which in turn can induce and regulate cellular senescence and can cause major changes in the metabolome [166]. In particular, an increase in mitochondrial oxygen consumption and oxidative phosphorylation have been reported in oncogene-induced senescence in human fibroblasts [166,167], oxidative stress-induced senescence [50,168], therapy-induced senescence in lymphoma [169], and DNA damage-induced senescence [50]. However, in replicative senescence, an impairment of mitochondrial function and increased glycolysis has been described [50,170].…”

Papel del péptido mitocondrial humanina como blanco terapéutico en cáncer y neurodegeneración

“…La senescencia celular tendría tanto efectos benéficos como perjudiciales dependiendo del contexto (66), teniendo un papel con-trovertido en el desarrollo del cáncer (67). Entre las desventajas, el fenotipo secretor asociado a la senescencia (SASP) puede perturbar el microambiente, alterar la estructura y el funcionamiento de los tejidos normales, y promover fenotipos malignos en células cercanas.…”