Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis
Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis
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DOI：
10.1016/j.celrep.2022.110444
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发表时间：
2022-03-01
期刊：
影响因子：
8.8
通讯作者：
Yoshimori, Tamotsu
中科院分区：
文献类型：
--
作者：
Yamamoto-Imoto, Hitomi;Minami, Satoshi;Yoshimori, Tamotsu
衰老细胞的积累会影响机体衰老和年龄相关疾病的患病率。新的证据表明，自噬的激活可以预防与年龄相关的疾病并延长寿命，但自噬在细胞衰老中的作用和调节机制尚不清楚。在这里，我们确定转录因子 MondoA 作为细胞衰老、自噬和线粒体稳态的调节剂。 MondoA 通过激活自噬来防止细胞衰老，部分通过抑制自噬负调节因子 Rubicon 来实现。此外，我们确定过氧化还原蛋白 3 (Prdx3) 是线粒体必需的 MondoA 的另一个下游调节因子！稳态和自噬。 Rubicon 和 Prdx3 独立发挥作用来调节衰老。此外，我们发现 MondoA 敲除小鼠在缺血性急性肾损伤（AKI）期间加剧了衰老，并且细胞核中 MondoA 的减少与人类衰老和缺血性 AKI 相关。我们的结果表明 MondoA 的减少会恶化衰老和与年龄相关的疾病。
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 mitochondria! homeo- stasis 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.