Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction.
Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction.
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DOI：
10.1038/s42003-020-01566-0
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发表时间：
2021-01-04
影响因子：
5.9
通讯作者：
Kwon HJ
中科院分区：
文献类型：
--
作者：
Kim D;Hwang HY;Ji ES;Kim JY;Yoo JS;Kwon HJ
细胞自噬是细胞内环境稳定的关键调节因子，自噬紊乱导致许多人类疾病。由于自噬在代谢失调中的作用，需要鉴定自噬调节剂作为治疗靶点。为了解决这一需求，我们进行了一个基于自噬表型的筛选，并确定了天然化合物山奈素（Kaem）作为自噬增强剂。Kaem通过转录因子EB（TFEB）的易位促进自噬，而没有MTOR干扰，表明其用于施用是安全的。此外，Kaem在体外以溶酶体活性依赖性方式加速脂滴降解，并改善饮食诱导的肥胖小鼠模型中的代谢失调。为了阐明Kaem的生物活性的机制，通过结合药物亲和力响应靶标稳定性和LC-MS/MS分析来鉴定靶蛋白。Kaem直接与线粒体延伸因子TUFM相互作用，TUFM的缺乏逆转Kaem诱导的自噬和脂质降解。Kaem还诱导线粒体活性氧（mtROS），从而促进溶酶体Ca 2+流出、TFEB易位和自噬诱导，表明TUFM在mtROS调节中的作用。总的来说，这些结果表明，Kaem是一种潜在的治疗候选/化学工具，用于治疗代谢失调，并揭示了TUFM在自噬中的作用，用于脂质过载的代谢调节。Kim，Hwang等人使用自噬障碍/代谢功能障碍的体外和体内模型来表明，在这种情况下，天然化合物山柰素是自噬增强剂，并揭示了控制这一点的潜在机制之一是由线粒体延伸因子TUFM介导的。这一见解可能在代谢紊乱的治疗中具有治疗价值。
Disorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem’s biological activity, the target protein was identified via combined drug affinity responsive target stability and LC–MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload. Kim, Hwang et al. use in vitro and in vivo models of autophagy disorder/metabolic dysfunction to show that in this context, the natural compound kaempferide is an autophagy enhancer and reveal that one of the underlying mechanisms governing this is mediated by the mitochondrial elongation factor TUFM. This insight may have therapeutic value in the treatment of metabolic disorders.
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伴侣介导的自噬的时代的到来。
DOI：
10.1038/s41580-018-0001-6
发表时间：
2018-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Kaushik S;Cuervo AM
通讯作者：
Cuervo AM
影响因子：
5.2
作者：
Kim TY;Ji ES;Lee JY;Kim JY;Yoo JS;Szasz AM;Dome B;Marko-Varga G;Kwon HJ
通讯作者：
Kwon HJ
影响因子：
64.5
作者：
Green DR;Levine B
通讯作者：
Levine B
影响因子：
5.3
作者：
Kim, Jong In;Huh, Jin Young;Kim, Jae Bum
通讯作者：
Kim, Jae Bum
EGFR靶向的MAB疗法通过NLRX1-TUFM蛋白复合物调节头部和颈部鳞状细胞癌的自噬调节。
影响因子：
8
作者：
Lei Y;Kansy BA;Li J;Cong L;Liu Y;Trivedi S;Wen H;Ting JP;Ouyang H;Ferris RL
通讯作者：
Ferris RL