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Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging.

Ziegler DV, Wiley CD, Velarde MC - Aging Cell (2014)

Bottom Line: Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases.We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence.Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.

View Article: PubMed Central - PubMed

Affiliation: Département de Biologie, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, Lyon, 69007, France; Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.

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Perturbation of mitochondrial homeostasis promotes the establishment and maintenance of cellular senescence during aging. Mitochondria are damaged over time leading to perturbation of mitochondrial homeostasis. Loss of proper mitochondrial homeostasis can promote cellular senescence through (1) excessive ROS production (orange), (2) impaired mitochondrial dynamics (brown), (3) electron transport chain defect (blue), (4) bioenergetics imbalance and increased AMPK activity (red), (5) decreased mitochondrial NAD+ and altered metabolism (green), and (6) mitochondrial calcium accumulation (purple). These mitochondrial signals trigger p53/p21 and/or p16/pRb pathways and ultimately lead to cellular senescence, which subsequently promotes age-related phenotypes, such as loss of tissue regeneration and function.
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fig01: Perturbation of mitochondrial homeostasis promotes the establishment and maintenance of cellular senescence during aging. Mitochondria are damaged over time leading to perturbation of mitochondrial homeostasis. Loss of proper mitochondrial homeostasis can promote cellular senescence through (1) excessive ROS production (orange), (2) impaired mitochondrial dynamics (brown), (3) electron transport chain defect (blue), (4) bioenergetics imbalance and increased AMPK activity (red), (5) decreased mitochondrial NAD+ and altered metabolism (green), and (6) mitochondrial calcium accumulation (purple). These mitochondrial signals trigger p53/p21 and/or p16/pRb pathways and ultimately lead to cellular senescence, which subsequently promotes age-related phenotypes, such as loss of tissue regeneration and function.

Mentions: Cellular senescence is accompanied by an increase in cell size (Hayflick & Moorhead, 1961), lysosomal content (Kurz et al., 2000), and senescence-associated β-galactosidase (SA-βgal) activity (Dimri et al., 1995; Kurz et al., 2000). It is associated with decreased nuclear expression of lamin B1 (Freund et al., 2012) and release of high-mobility group box 1 (HMGB1) proteins (Davalos et al., 2013). It is often correlated with the presence of nuclear DNA damage foci (Rodier et al., 2009) and chromatin alterations (Narita et al., 2003). It is induced by multiple factors, such as repeated cell culture, telomere attrition, irradiation, oncogene activation, and oxidative damage (Hayflick & Moorhead, 1961; Campisi & D'Adda di Fagagna, 2007). It can also be caused by the perturbation of mitochondrial homeostasis (Fig. 1), which may accelerate age-related phenotypes (Sahin & DePinho, 2010, 2012). While several studies already show that mitochondrial defects can promote cellular senescence (Passos et al., 2007; Moiseeva et al., 2009; Velarde et al., 2012), the mechanisms involved in this regulation are poorly understood. Because mitochondria can generate ROS (Quinlan et al., 2013), it is proposed that excessive mitochondrial ROS is important to establish cellular senescence. This has been an attractive model because of its consistency with the free radical theory of aging. However, other mitochondrial factors may be equally or even more important to induce cellular senescence.


Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging.

Ziegler DV, Wiley CD, Velarde MC - Aging Cell (2014)

Perturbation of mitochondrial homeostasis promotes the establishment and maintenance of cellular senescence during aging. Mitochondria are damaged over time leading to perturbation of mitochondrial homeostasis. Loss of proper mitochondrial homeostasis can promote cellular senescence through (1) excessive ROS production (orange), (2) impaired mitochondrial dynamics (brown), (3) electron transport chain defect (blue), (4) bioenergetics imbalance and increased AMPK activity (red), (5) decreased mitochondrial NAD+ and altered metabolism (green), and (6) mitochondrial calcium accumulation (purple). These mitochondrial signals trigger p53/p21 and/or p16/pRb pathways and ultimately lead to cellular senescence, which subsequently promotes age-related phenotypes, such as loss of tissue regeneration and function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4310776&req=5

fig01: Perturbation of mitochondrial homeostasis promotes the establishment and maintenance of cellular senescence during aging. Mitochondria are damaged over time leading to perturbation of mitochondrial homeostasis. Loss of proper mitochondrial homeostasis can promote cellular senescence through (1) excessive ROS production (orange), (2) impaired mitochondrial dynamics (brown), (3) electron transport chain defect (blue), (4) bioenergetics imbalance and increased AMPK activity (red), (5) decreased mitochondrial NAD+ and altered metabolism (green), and (6) mitochondrial calcium accumulation (purple). These mitochondrial signals trigger p53/p21 and/or p16/pRb pathways and ultimately lead to cellular senescence, which subsequently promotes age-related phenotypes, such as loss of tissue regeneration and function.
Mentions: Cellular senescence is accompanied by an increase in cell size (Hayflick & Moorhead, 1961), lysosomal content (Kurz et al., 2000), and senescence-associated β-galactosidase (SA-βgal) activity (Dimri et al., 1995; Kurz et al., 2000). It is associated with decreased nuclear expression of lamin B1 (Freund et al., 2012) and release of high-mobility group box 1 (HMGB1) proteins (Davalos et al., 2013). It is often correlated with the presence of nuclear DNA damage foci (Rodier et al., 2009) and chromatin alterations (Narita et al., 2003). It is induced by multiple factors, such as repeated cell culture, telomere attrition, irradiation, oncogene activation, and oxidative damage (Hayflick & Moorhead, 1961; Campisi & D'Adda di Fagagna, 2007). It can also be caused by the perturbation of mitochondrial homeostasis (Fig. 1), which may accelerate age-related phenotypes (Sahin & DePinho, 2010, 2012). While several studies already show that mitochondrial defects can promote cellular senescence (Passos et al., 2007; Moiseeva et al., 2009; Velarde et al., 2012), the mechanisms involved in this regulation are poorly understood. Because mitochondria can generate ROS (Quinlan et al., 2013), it is proposed that excessive mitochondrial ROS is important to establish cellular senescence. This has been an attractive model because of its consistency with the free radical theory of aging. However, other mitochondrial factors may be equally or even more important to induce cellular senescence.

Bottom Line: Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases.We emphasize that multiple mitochondrial signaling pathways, besides mitochondrial ROS, can induce cellular senescence.Together, these pathways provide a broader perspective for studying the contribution of mitochondrial stress to aging, linking mitochondrial dysfunction and aging through the process of cellular senescence.

View Article: PubMed Central - PubMed

Affiliation: Département de Biologie, Ecole Normale Supérieure de Lyon, 46 allée d'Italie, Lyon, 69007, France; Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA, 94945, USA.

Show MeSH
Related in: MedlinePlus