Abstract
Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.
Highlights
Autophagy is essential for cellular homeostasis and adaptation to stress, and dysregulation of autophagy affects tissue homeostasis and individual health (Leidal et al, 2018)
Decline of autophagy accelerates cellular senescence Since roles of autophagy during cellular senescence are unclear (Leidal et al, 2018; Kang et al, 2015; Young et al, 2009; Narita et al, 2011; Dou et al, 2015), we first investigated autophagic activity using two types of senescent cells: human retinal pigment epithelial cell line induced with a genotoxic agent, doxorubicin (DXR) (DNA damage-induced senescence), and TIG-3 cells induced by replication
Autophagic activity determined by LC3 autophagic flux (Mizushima et al, 2010) was decreased in both DNA damage-induced and replicative senescence (Figures 1C and S1D), suggesting that autophagy is involved in cellular senescence
Summary
Autophagy is essential for cellular homeostasis and adaptation to stress, and dysregulation of autophagy affects tissue homeostasis and individual health (Leidal et al, 2018). While it has been shown that autophagic activity decreases with organismal aging, a growing body of evidence implicates the activation of autophagy in promoting longevity and preventing age-associated phenotypes (Fernandez et al, 2018, Barzilai et al, 2016; Baur et al, 2006; Eisenberg et al, 2016; Lamming et al, 2013). Introduction of mutation in one of the other Atgs, Beclin, which causes constitutive activation of autophagy, promotes longevity and prevents age-associated phenotypes in mice (Fernandez et al, 2018). Article ll and prevents age-associated kidney fibrosis and neurodegenerative disease in mice (Nakamura et al, 2019). The expression of Rubicon increases with age in C. elegans, Drosophila, and several mouse tissues including kidney and liver (Tanaka et al, 2016; Nakamura et al, 2019), suggesting that an increase of Rubicon could be one of the causes of age-dependent autophagic declines.
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