Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

By Christopher D. Wiley, Michael C. Velarde, Pacome Lecot, Su Liu, E. A. Sarnoski, Adam Freund, Kotaro Shirakawa, H. Lim, Sonnet S. Davis, A. Ramanathan and 3 more. Cell Metabolism, 2015

1,109 citations recorded by the source corpus.

SUMMARY Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

Subfields: Epidemiology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/1ebfdd0b2d549a8871c9eade659aff20ef002c08

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Citations in the corpus

Measuring biological aging in humans: A quest (2019, positive): “…et al., 2016; GonzalesEbsen, Gregersen, & Olsen, 2017; Hall et al., 2017; Herranz & Gil, 2018; Kang et al., 2015; Ligthart et al., 2016; Mills, Kelly, & O'Neill, 2017; Moreno-Blas, Gorostieta-Salas, & Castro-Obregón, 2018; Netea-Maier, Plantinga, Veerdonk, Smit, & Netea, 2015; Wiley et al., 2016).”
Cellular Senescence: Defining a Path Forward. (2019, background): “Mouse models of mitochondrial dysfunction and enhanced oxidative stress show increased senescence (Wiley et al., 2016), but a detailed characterization of mitochondrial function in senescent cells in vivo is lacking.”
Mitochondrial dysfunction in cell senescence and aging (2022, background): “While neither increased ROS nor cell senescence was observed in the original publications, this was later rectified (58), and a specific type of cell senescence missing the proinflammatory arm of the SASP was found in adipose tissue of PolG mutator mice, which rapidly accumulate mtDNA mutations (59)”
Metabolic Control of Longevity. (2016, background): “Although MiDAS appears to be rather frequent in homozygous Polg mice, which have a progeroid phenotype linked to an increased rate of mitochondrial DNA mutations (Wiley et al., 2016), the exact contribution of this phenomenon to the aging process remains to be determined.”
Cellular Senescence: A Translational Perspective (2017, background): “…on the cell type from which senescent cells originated, how senescence was induced, hormonal milieu, and presence of drugs including glucocorticoids, rapamycin, metformin, or JAK1/2 inhibitors (Xu et al., 2015b, Wiley et al., 2016; Laberge et al., 2012; Moiseeva et al., 2013; Laberge et al., 2015).”
Mechanisms and functions of cellular senescence. (2018, neutral): “For example, a distinct senescent secretome has been described in the context of mitochondrial dysfunction (95), and NOTCH signaling enables a switch between a TGF-β and an inflammatory secretome (60). graft transplants (69, 70).”
Hallmarks of Cellular Senescence. (2018, positive): “The phenotype, particularly the SASP, appears to be characteristic of this type of senescence [56].”
Senescence and the SASP: many therapeutic avenues (2020, background): “Metabolic fluctuations, such as altered nicotinamide adenine dinucleotide (NAD+) to NADH ratios, underlie the MiDAS SASP by influencing 5′AMP-activated protein kinase (AMPK)mediated activation of p53 (Wiley et al. 2016).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “Furthermore, can we leverage what we have learnt about anti-viral signalling during cell death to enhance anti-cancer therapy by inhibiting caspases? Likewise, will our understanding of how mtDNA and STING function in neurodegeneration lead to novel therapeutic strategies to enhance healthy ageing [”
Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances (2025, positive): “263 Under hyperglycemic conditions, overexpression of mitochondrial uncoupling protein 2 induced the up-regulation of NAD + and SIRT3, and alleviated senescence caused by hyperglycemia.”