Mitochondrial dysfunction and cell senescence: deciphering a complex relationship

Abstract

Cellular senescence and mitochondrial dysfunction have both been defined as classical hallmarks of the ageing process. Here, we review the intricate relationship between the two. In the context of ageing, it is now well regarded that cellular senescence is a key driver in both ageing and the onset of a number of age‐related pathologies. Emerging evidence has pinpointed mitochondria as one of the key modulators in the development of the senescence phenotype, particularly the pro‐inflammatory senescence associated secretory phenotype (SASP). This review focuses on the contribution of homeostatic mechanisms, as well as of reactive oxygen species and mitochondrial metabolites in the senescence programme. Furthermore, we discuss emerging pathways and mitochondrial‐mediated mechanisms that may be influencing the SASP and, subsequently, explore how these may be exploited to open up new therapeutic avenues.

The Spectrum of Reactive Cholangiocytes in Primary Sclerosing Cholangitis

“…Cellular senescence can be triggered by several stressor events, including repeated cell division and strong mitogenic signals, telomere shortening, DNA damage, and chromatin remodeling, which activate the p53 and p16 INK4a tumor suppressor pathways that initiate the senescence response . Acute, short‐lived senescence is a physiological cellular checkpoint that targets a specific cell population, usually damaged and/or unwanted cells, with the aim of preventing the proliferation of cells with potentially oncogenic DNA damage, marking them for elimination by immune cells, and mobilizing progenitor cells to reestablish cell numbers . However, chronic senescence develops from repeated, prolonged exposure to stressors and results in an accumulation of senescent cells due to the impaired ability of these cells to be removed and replaced.…”

“…(10) Acute, short-lived senescence is a physiological cellular checkpoint that targets a specific cell population, usually damaged and/or unwanted cells, with the aim of preventing the proliferation of cells with potentially oncogenic DNA damage, marking them for elimination by immune cells, and mobilizing progenitor cells to reestablish cell numbers. (11) However, chronic senescence develops from repeated, prolonged exposure to stressors and results in an accumulation of senescent cells due to the impaired ability of these cells to be removed and replaced. Moreover, aRtICle INFoRMatIoN: senescent cells frequently exhibit a hypersecretory state known as the "senescence-associated secretory phenotype" (SASP), composed of cytokines, chemokines, growth factors, proteases, and extracellular matrix factors, which can reinforce and maintain the process of senescence and be detrimental to the ability of tissues to function normally.…”

Mitochondrial localization of SESN2

“…Mitochondrial respiration is the major source of ATP but this process is also associated with leakage of electrons from the respiratory chain that lead to production of superoxide and other types of ROS [36]. Although at moderate levels ROS might play some signaling roles stimulating regulatory pathways involved in cell proliferation [37], exuberant accumulation of ROS causes damages of different types of macromolecules and compromise different physiological processes that can lead to senescence and cell death [38,39].…”

Mitochondria could be a potential key mediator linking the intestinal microbiota to depression

“…Dysfunctional mitochondria produce high levels of ROS that cannot be controlled, leading to macromolecular damage and cellular senescence. 54,55 Particularly, these cells secret proinflammatory cytokines called senescence-associated secretory phenotype (SASP), which can accelerate the cells' further senescence (autocrine effect) or induce other cells' senescence (paracrine effect). 53 In senescent cells, it has been reported that cell cycle arrest occurs with increased gene expression of p16, ARF, p21, and p53 and decreased proliferation marker Ki67.…”