Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

Yamamoto-Imoto, Hitomi; Minami, Satoshi; Shioda, Tatsuya; Yamashita, Yurina; Sakai, Shinsuke; Maeda, Shihomi; Yamamoto, Takeshi; Oki, Shinya; Takashima, Misako; Yamamuro, Tadashi; Yanagawa, Kyosuke; Edahiro, Ryuya; Iwatani, Miki; So, Mizue; Tokumura, Ayaka; Abe, Toyofumi; Imamura, Ryoichi; Nonomura, Norio; Okada, Yukinori; Ayer, Donald E.; Ogawa, Hidesato; Hara, Eiji; Takabatake, Yoshitsugu; Isaka, Yoshitaka; Nakamura, Shuhei; Yoshimori, Tamotsu

doi:10.1016/j.celrep.2022.110444

Cited by 42 publications

(36 citation statements)

References 84 publications

(113 reference statements)

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“…Although both canonical autophagy and LAP result in the lipidation of LC3-I to form LC3-II, LAP is controlled by some, but not all, members of the autophagy machinery [ 66 , 67 ]. Of relevance, LAP is stimulated by Rubicon, an autophagy-negative regulator, able to act on Beclin-1 [ 66 , 69 , 70 ]. This would imply antagonistic roles for SPD (stimulating autophagy) and Rubicon (stimulating LAP).…”

Section: Discussionmentioning

confidence: 99%

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Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

et al. 2022

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Impaired autophagy, responsible for increased inflammation, constitutes a risk factor for the more severe COVID-19 outcomes. Spermidine (SPD) is a known autophagy modulator and supplementation for COVID-19 risk groups (including the elderly) is recommended. However, information on the modulatory effects of eugenol (EUG) is scarce. Therefore, the effects of SPD and EUG, both singularly and in combination, on autophagy were investigated using different cell lines (HBEpiC, SHSY5Y, HUVEC, Caco-2, L929 and U937). SPD (0.3 mM), EUG (0.2 mM) and 0.3 mM SPD + 0.2 mM EUG, significantly increased autophagy using the hallmark measure of LC3-II protein accumulation in the cell lines without cytotoxic effects. Using Caco-2 cells as a model, several crucial autophagy proteins were upregulated at all stages of autophagic flux in response to the treatments. This effect was verified by the activation/differentiation and migration of U937 monocytes in a three-dimensional reconstituted intestinal model (Caco-2, L929 and U937 cells). Comparable benefits of SPD, EUG and SPD + EUG in inducing autophagy were shown by the protection of Caco-2 and L929 cells against lipopolysaccharide-induced inflammation. SPD + EUG is an innovative dual therapy capable of stimulating autophagy and reducing inflammation in vitro and could show promise for COVID-19 risk groups.

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Section: Discussionmentioning

confidence: 99%

“…Given that the regulatory mechanisms of LAP and autophagy are not well understood [ 70 ], it would be important to establish whether LAP induced phagocytosis is involved in removing SARS-CoV-2. Thereafter, it would be important to establish the effect of SPD and EUG on both LAP and canonical autophagy in the presence of viral infection.…”

Section: Discussionmentioning

confidence: 99%

Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

et al. 2022

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“…In addition to PRX1, the role of PRX3 in aging was explored in a recent study [ 86 ]. Previous studies already demonstrated that PRX3 is essential for maintaining mitochondrial function by maintaining mitochondrial redox homeostasis [ 87 , 88 ].…”

Section: Roles Of Peroxiredoxins In Agingmentioning

confidence: 99%

“…Previous studies already demonstrated that PRX3 is essential for maintaining mitochondrial function by maintaining mitochondrial redox homeostasis [ 87 , 88 ]. This study demonstrated that the expression level of PRX3 is regulated by an age-associated glucose-responsive transcription factor MondoA in two in vitro senescence models—DNA-damage-induced senescence by doxorubicin-treated human retinal pigment epithelial cells and replicative senescence by TIG-3 cells [ 86 ]. The expression level of MondoA decreases with age that drives cellular senescence by impaired mitochondrial homeostasis through the expression of PRX3 [ 86 ].…”

Section: Roles Of Peroxiredoxins In Agingmentioning

confidence: 99%

“…This study demonstrated that the expression level of PRX3 is regulated by an age-associated glucose-responsive transcription factor MondoA in two in vitro senescence models—DNA-damage-induced senescence by doxorubicin-treated human retinal pigment epithelial cells and replicative senescence by TIG-3 cells [ 86 ]. The expression level of MondoA decreases with age that drives cellular senescence by impaired mitochondrial homeostasis through the expression of PRX3 [ 86 ]. In agreement with this finding, muscle-specific overexpression of PRX3 can attenuate contractile dysfunction and muscle atrophy in a SOD1 KO mouse model of accelerated sarcopenia by improving mitochondrial function [ 71 ].…”

Section: Roles Of Peroxiredoxins In Agingmentioning

confidence: 99%

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Peroxiredoxin, Senescence, and Cancer

Deng

Chan

et al. 2022

Cells

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Peroxiredoxins are multifunctional enzymes that play a key role in protecting cells from stresses and maintaining the homeostasis of many cellular processes. Peroxiredoxins were firstly identified as antioxidant enzymes that can be found in all living organisms. Later studies demonstrated that peroxiredoxins also act as redox signaling regulators, chaperones, and proinflammatory factors and play important roles in oxidative defense, redox signaling, protein folding, cycle cell progression, DNA integrity, inflammation, and carcinogenesis. The versatility of peroxiredoxins is mainly based on their unique active center cysteine with a wide range of redox states and the ability to switch between low- and high-molecular-weight species for regulating their peroxidase and chaperone activities. Understanding the molecular mechanisms of peroxiredoxin in these processes will allow the development of new approaches to enhance longevity and to treat various cancers. In this article, we briefly review the history of peroxiredoxins, summarize recent advances in our understanding of peroxiredoxins in aging- and cancer-related biological processes, and discuss the future perspectives of using peroxiredoxins in disease diagnostics and treatments.

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Body‐Wide Inactivation of the Myc‐Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence

Wang,

Stevens,

et al. 2024

Advanced Science

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The “Mlx” and “Myc” transcription factor networks cross‐communicate and share many common gene targets. Myc's activity depends upon its heterodimerization with Max, whereas the Mlx Network requires that the Max‐like factor Mlx associate with the Myc‐like factors MondoA or ChREBP. The current work demonstrates that body‐wide Mlx inactivation, like that of Myc, accelerates numerous aging‐related phenotypes pertaining to body habitus and metabolism. The deregulation of numerous aging‐related Myc target gene sets is also accelerated. Among other functions, these gene sets often regulate ribosomal and mitochondrial structure and function, genomic stability, and aging. Whereas “MycKO” mice have an extended lifespan because of a lower cancer incidence, “MlxKO” mice have normal lifespans and a higher cancer incidence. Like Myc, the expression of Mlx, MondoA, and ChREBP and their control over their target genes deteriorate with age in both mice and humans. Collectively, these findings underscore the importance of lifelong and balanced cross‐talk between the two networks to maintain proper function and regulation of the many factors that can affect normal aging.

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Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis

Cited by 42 publications

References 84 publications

Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

Wheat Germ Spermidine and Clove Eugenol in Combination Stimulate Autophagy In Vitro Showing Potential in Supporting the Immune System against Viral Infections

Peroxiredoxin, Senescence, and Cancer

Body‐Wide Inactivation of the Myc‐Like Mlx Transcription Factor Network Accelerates Aging and Increases the Lifetime Cancer Incidence

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