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Spotlight
Mitochondrial Dysfunction Meets Senescence Suchira Gallage1 and Jesús Gil1,* Cellular senescence and mitochondrial dysfunction are hallmarks of ageing, but until now their relationship has not been clear. Recent work by Wiley et al. shows that mitochondrial defects can cause a distinct senescence phenotype termed MiDAS (mitochondrial dysfunction-associated senescence). MiDAS has a specific secretome that is able to drive some of the aging phenotypes. These findings suggest novel therapeutic opportunities for treating age-related pathologies. Ageing is the single largest risk factor for cancer and degenerative diseases, which has boosted interest in understanding the underlying mechanisms regulating it. Targeting these mechanisms could simultaneously delay several age-related pathologies and improve general healthspan. With this aim, hallmarks of ageing have been identified [1], such as mitochondrial dysfunction or cellular senescence, which is the irreversible arrest that can be triggered by telomere shortening and a variety of stresses. Mounting evidence suggests a dynamic relationship between aberrant mitochondria and senescence [2,3]. A recent study [4] confirms that mitochondrial dysfunction causes a distinct type of cellular senescence. This link is conserved across different cellular models and in progeroid mice, which could explain some ageing phenotypes.
[5]. With this in mind, Wiley et al. [4] screened the mammalian SIRTs and identified that knockdown of the mitochondrial SIRTs, SIRT3 or SIRT5, can induce senescence. Moreover, disrupting mitochondrial function in alternative ways, such as treatment with ethidium bromide or the electron transport chain inhibitor rotenone, also caused senescence. Senescence is a stress response that limits the proliferation of damaged and aberrant cells [6]. Senescence is a complex programme: besides the growth arrest, senescent cells undergo many other changes such as metabolic reprogramming, they suffer nuclear and chromatin alterations, and they secrete a complex mixture of secreted factors that range from [8_TD$IF]proinflammatory cytokines and chemokines to growth factors and proteases, collectively referred to as the senescenceassociated secretory phenotype (SASP). Wiley et al. [4] observed that besides the stable arrest, cells with mitochondrial dysfunction have other hallmarks of senescence including the presence of senescence-associated b-galactosidase activity (SA-b-Gal) or reduced expression of lamin B1. However, there were differences when compared with cells undergoing senescence by genotoxic stress; most notably, they did not secrete inflammatory components such as [9_TD$IF]interleukin (IL)6, IL[10_TD$IF]8, or IL1b, which are core components of the SASP (Figure 1).
the expression of the SASP. Here they suggest that it does so by an NF-kB-independent mechanism that results in the loss of the IL1-dependent inflammatory arm of the SASP and in the expression of other factors such as IL10, TNF/[1_TD$IF], and CCL27. Many paracrine effects attributed to senescent cells in cancer and ageing are exerted by the SASP. Thus, given that the composition of the SASP and the secretome of MiDAS cells differed, it was important to study their paracrine effects. Interestingly, the secretome of MiDAS can suppress preadipocyte differentiation and promote keratinocyte differentiation, potentially explaining the lipodystrophy and skin phenotypes often observed in aged mice. To understand the implications of MiDAS on ageing, the authors use the POLGD257A progeroid mice. These mice express a form of mtDNA polymerase (PolG) with defective proofreading activity, which causes mutations on the mitochondrial DNA. As a result, increased numbers of senescent cells are detected in inguinal adipose tissue and in the stratum corneum (outer layer of the skin) by 8 months. Importantly, a MiDAS secretome (higher levels of IL-10 and TNF/ and no changes in IL1A, IL1B, and IL6) and a reduced NAD+[12_TD$IF]/NADH ratio were also observed. Although these results are in agreement with the phenotypes observed in cell culture, how much the POLGD257A mice resemble normal ageing is unclear. These mice accumulate higher levels of mtDNA mutations than observed in normal ageing. In addition, many pro-inflammatory factors that are absent from the MiDAS secretome increase during ageing as a result of chronic inflammation or inflammaging [7]. Whether the MiDAS secretome is observed during natural ageing, and under which circumstances, needs to be investigated.
Due to the differences in phenotypes, Wiley et al. [4] named this state mitochondrial dysfunction-associated senescence (MiDAS). The authors show that MiDAS was not caused by accumulation of nuclear DNA damage (53BP1 foci) or oxidative stress as previously thought [2,3]. MiDAS was instead caused by an increase in the ratio of NAD+[7_TD$IF]/NADH and the resulting activation of AMP-activated protein kinase (AMPK), which in turn activates p53 during MiDAS. Both the growth arrest and the modified secretome of MiDAS Sirtuins (SIRTs) are a family of proteins that cells were p53-dependent. The authors Defective mitochondria accumulate with regulate ageing from yeast to mammals have previously suggested that p53 limits age [8]. Identifying whether MiDAS occurs
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
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TIBS 1225 No. of Pages 3
Senescence SASP • IL1/NF-κB dependent components • IL1A, IL1B, IL6, IL8, etc.
Genotoxic or oncogenic stress • High NAD+/NADH • Low AMPK acvity • SASP • Stable growth arrest • SA-β-Gal acvity • Low Lamin B1
Pre-Adipocyte differenaon Keranocyte differenaon
• Low NAD+/NADH • High AMPK acvity • MiDAS secretome
Proliferang cell
MiDAS secretome Mitochondrial dysfuncon
• Absence of IL1/NF-κB secretome • IL10, TNFα, CCL27
• SIRT3 or SIRT5 KD • rho0 cells (ethidium bromide) • Rot or An A treatment • HSPA9 KD • POLGD257A
Mitochondrial dysfuncon associated-senescence (MiDAS)
Figure 1. Comparison between [1_TD$IF]Mitochondrial [2_TD$IF]Dysfunction [3_TD$IF]Associated-[4_TD$IF]Senescence (MiDAS) and [5_TD$IF]Stress-[6_TD$IF]Induced [4_TD$IF]Senescence. MiDAS is observed in different genetic backgrounds or in response to treatments that eliminate mitochondria or affect their function. Although MiDAS and senescence caused by genotoxic or oncogenic stress share defining characteristics, they differ in other aspects such as their secretomes. The MiDAS secretome lacks an IL1/NF-kB-dependent arm and has the ability to supress pre-adipocyte and promote keratinocyte differentiation.
during normal ageing would give insight into the physiological relevance of aberrant mitochondria and the MiDAS phenotype. Although senescence is defined as an irreversible cell arrest, the lack of an unequivocal combination of senescence markers means that the term has been applied loosely [9]. Whether MiDAS should come under the ‘umbrella’ term of senescence or needs to be classified differently will need to be settled. Although oncogenic and genotoxic stresses induce a similar secretory profile, and at least their core components are conserved, it is clear that the secretory profile of ‘senescent’ cells depends on different
2
factors, such as the senescence trigger also important modulators of the senesand the cell type. For example, a different cence phenotype. senescence-inflammatory response (SIR) was defined as the secretome of senescent 1Cell Proliferation Group, MRC Clinical Sciences Centre, cells with an active Wnt pathway [10]. Imperial College London, Hammersmith Campus, London The MiDAS secretome constitutes a W12 0NN, UK similar example of a different senescence *Correspondence: [email protected] (J. Gil). secretome. http://dx.doi.org/10.1016/j.tibs.2016.01.005 In summary[13_TD$IF], the work by Wiley et al. [4] shows how mitochondrial dysfunction induces senescence with a distinct secretory pattern, which is conserved in a progeroid mouse model. Besides increasing our understanding of the roles that senescence plays in ageing, this study suggests that mitochondria are not just a trigger but
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
References 1. Lopez-Otin, C. et al. (2013) The hallmarks of aging. Cell 153, 1194–1217 2. Passos, J.F. et al. (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomeredependent senescence. PLoS Biol. 5, e110 3. Moiseeva, O. et al. (2009) Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol. Cell. Biol. 29, 4495–4507 4. Wiley, C.D. et al. (2015) Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell
TIBS 1225 No. of Pages 3
Metab. Published online December 10, 2015. http://dx.doi. org/10.1016/j.cmet.2015.11.011 5. Haigis, M.C. and Sinclair, D.A. (2010) Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 6. Salama, R. et al. (2014) Cellular senescence and its effector programs. Genes Dev. 28, 99–114
7. Franceschi, C. and Campisi, J. (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A: Biol. Sci. Med. Sci. 69 (Suppl. 1), S4–S9 8. Herbst, A. et al. (2007) Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. J. Gerontol. A: Biol. Sci. Med. Sci. 62, 235–245
9. Sharpless, N.E. and Sherr, C.J. (2015) Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 10. Pribluda, A. et al. (2013) A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
3
Spotlight
Mitochondrial Dysfunction Meets Senescence Suchira Gallage1 and Jesús Gil1,* Cellular senescence and mitochondrial dysfunction are hallmarks of ageing, but until now their relationship has not been clear. Recent work by Wiley et al. shows that mitochondrial defects can cause a distinct senescence phenotype termed MiDAS (mitochondrial dysfunction-associated senescence). MiDAS has a specific secretome that is able to drive some of the aging phenotypes. These findings suggest novel therapeutic opportunities for treating age-related pathologies. Ageing is the single largest risk factor for cancer and degenerative diseases, which has boosted interest in understanding the underlying mechanisms regulating it. Targeting these mechanisms could simultaneously delay several age-related pathologies and improve general healthspan. With this aim, hallmarks of ageing have been identified [1], such as mitochondrial dysfunction or cellular senescence, which is the irreversible arrest that can be triggered by telomere shortening and a variety of stresses. Mounting evidence suggests a dynamic relationship between aberrant mitochondria and senescence [2,3]. A recent study [4] confirms that mitochondrial dysfunction causes a distinct type of cellular senescence. This link is conserved across different cellular models and in progeroid mice, which could explain some ageing phenotypes.
[5]. With this in mind, Wiley et al. [4] screened the mammalian SIRTs and identified that knockdown of the mitochondrial SIRTs, SIRT3 or SIRT5, can induce senescence. Moreover, disrupting mitochondrial function in alternative ways, such as treatment with ethidium bromide or the electron transport chain inhibitor rotenone, also caused senescence. Senescence is a stress response that limits the proliferation of damaged and aberrant cells [6]. Senescence is a complex programme: besides the growth arrest, senescent cells undergo many other changes such as metabolic reprogramming, they suffer nuclear and chromatin alterations, and they secrete a complex mixture of secreted factors that range from [8_TD$IF]proinflammatory cytokines and chemokines to growth factors and proteases, collectively referred to as the senescenceassociated secretory phenotype (SASP). Wiley et al. [4] observed that besides the stable arrest, cells with mitochondrial dysfunction have other hallmarks of senescence including the presence of senescence-associated b-galactosidase activity (SA-b-Gal) or reduced expression of lamin B1. However, there were differences when compared with cells undergoing senescence by genotoxic stress; most notably, they did not secrete inflammatory components such as [9_TD$IF]interleukin (IL)6, IL[10_TD$IF]8, or IL1b, which are core components of the SASP (Figure 1).
the expression of the SASP. Here they suggest that it does so by an NF-kB-independent mechanism that results in the loss of the IL1-dependent inflammatory arm of the SASP and in the expression of other factors such as IL10, TNF/[1_TD$IF], and CCL27. Many paracrine effects attributed to senescent cells in cancer and ageing are exerted by the SASP. Thus, given that the composition of the SASP and the secretome of MiDAS cells differed, it was important to study their paracrine effects. Interestingly, the secretome of MiDAS can suppress preadipocyte differentiation and promote keratinocyte differentiation, potentially explaining the lipodystrophy and skin phenotypes often observed in aged mice. To understand the implications of MiDAS on ageing, the authors use the POLGD257A progeroid mice. These mice express a form of mtDNA polymerase (PolG) with defective proofreading activity, which causes mutations on the mitochondrial DNA. As a result, increased numbers of senescent cells are detected in inguinal adipose tissue and in the stratum corneum (outer layer of the skin) by 8 months. Importantly, a MiDAS secretome (higher levels of IL-10 and TNF/ and no changes in IL1A, IL1B, and IL6) and a reduced NAD+[12_TD$IF]/NADH ratio were also observed. Although these results are in agreement with the phenotypes observed in cell culture, how much the POLGD257A mice resemble normal ageing is unclear. These mice accumulate higher levels of mtDNA mutations than observed in normal ageing. In addition, many pro-inflammatory factors that are absent from the MiDAS secretome increase during ageing as a result of chronic inflammation or inflammaging [7]. Whether the MiDAS secretome is observed during natural ageing, and under which circumstances, needs to be investigated.
Due to the differences in phenotypes, Wiley et al. [4] named this state mitochondrial dysfunction-associated senescence (MiDAS). The authors show that MiDAS was not caused by accumulation of nuclear DNA damage (53BP1 foci) or oxidative stress as previously thought [2,3]. MiDAS was instead caused by an increase in the ratio of NAD+[7_TD$IF]/NADH and the resulting activation of AMP-activated protein kinase (AMPK), which in turn activates p53 during MiDAS. Both the growth arrest and the modified secretome of MiDAS Sirtuins (SIRTs) are a family of proteins that cells were p53-dependent. The authors Defective mitochondria accumulate with regulate ageing from yeast to mammals have previously suggested that p53 limits age [8]. Identifying whether MiDAS occurs
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
1
TIBS 1225 No. of Pages 3
Senescence SASP • IL1/NF-κB dependent components • IL1A, IL1B, IL6, IL8, etc.
Genotoxic or oncogenic stress • High NAD+/NADH • Low AMPK acvity • SASP • Stable growth arrest • SA-β-Gal acvity • Low Lamin B1
Pre-Adipocyte differenaon Keranocyte differenaon
• Low NAD+/NADH • High AMPK acvity • MiDAS secretome
Proliferang cell
MiDAS secretome Mitochondrial dysfuncon
• Absence of IL1/NF-κB secretome • IL10, TNFα, CCL27
• SIRT3 or SIRT5 KD • rho0 cells (ethidium bromide) • Rot or An A treatment • HSPA9 KD • POLGD257A
Mitochondrial dysfuncon associated-senescence (MiDAS)
Figure 1. Comparison between [1_TD$IF]Mitochondrial [2_TD$IF]Dysfunction [3_TD$IF]Associated-[4_TD$IF]Senescence (MiDAS) and [5_TD$IF]Stress-[6_TD$IF]Induced [4_TD$IF]Senescence. MiDAS is observed in different genetic backgrounds or in response to treatments that eliminate mitochondria or affect their function. Although MiDAS and senescence caused by genotoxic or oncogenic stress share defining characteristics, they differ in other aspects such as their secretomes. The MiDAS secretome lacks an IL1/NF-kB-dependent arm and has the ability to supress pre-adipocyte and promote keratinocyte differentiation.
during normal ageing would give insight into the physiological relevance of aberrant mitochondria and the MiDAS phenotype. Although senescence is defined as an irreversible cell arrest, the lack of an unequivocal combination of senescence markers means that the term has been applied loosely [9]. Whether MiDAS should come under the ‘umbrella’ term of senescence or needs to be classified differently will need to be settled. Although oncogenic and genotoxic stresses induce a similar secretory profile, and at least their core components are conserved, it is clear that the secretory profile of ‘senescent’ cells depends on different
2
factors, such as the senescence trigger also important modulators of the senesand the cell type. For example, a different cence phenotype. senescence-inflammatory response (SIR) was defined as the secretome of senescent 1Cell Proliferation Group, MRC Clinical Sciences Centre, cells with an active Wnt pathway [10]. Imperial College London, Hammersmith Campus, London The MiDAS secretome constitutes a W12 0NN, UK similar example of a different senescence *Correspondence: [email protected] (J. Gil). secretome. http://dx.doi.org/10.1016/j.tibs.2016.01.005 In summary[13_TD$IF], the work by Wiley et al. [4] shows how mitochondrial dysfunction induces senescence with a distinct secretory pattern, which is conserved in a progeroid mouse model. Besides increasing our understanding of the roles that senescence plays in ageing, this study suggests that mitochondria are not just a trigger but
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
References 1. Lopez-Otin, C. et al. (2013) The hallmarks of aging. Cell 153, 1194–1217 2. Passos, J.F. et al. (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomeredependent senescence. PLoS Biol. 5, e110 3. Moiseeva, O. et al. (2009) Mitochondrial dysfunction contributes to oncogene-induced senescence. Mol. Cell. Biol. 29, 4495–4507 4. Wiley, C.D. et al. (2015) Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell
TIBS 1225 No. of Pages 3
Metab. Published online December 10, 2015. http://dx.doi. org/10.1016/j.cmet.2015.11.011 5. Haigis, M.C. and Sinclair, D.A. (2010) Mammalian sirtuins: biological insights and disease relevance. Annu. Rev. Pathol. 5, 253–295 6. Salama, R. et al. (2014) Cellular senescence and its effector programs. Genes Dev. 28, 99–114
7. Franceschi, C. and Campisi, J. (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A: Biol. Sci. Med. Sci. 69 (Suppl. 1), S4–S9 8. Herbst, A. et al. (2007) Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss. J. Gerontol. A: Biol. Sci. Med. Sci. 62, 235–245
9. Sharpless, N.E. and Sherr, C.J. (2015) Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 10. Pribluda, A. et al. (2013) A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell 24, 242–256
Trends in Biochemical Sciences, Month Year, Vol. xx, No. yy
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