AMPK 在调节不同的有丝分裂途径中发挥着相反的作用

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2024-11-11 DOI:10.1016/j.molcel.2024.10.025

Marianna Longo, Aniketh Bishnu, Pierpaolo Risiglione, Lambert Montava-Garriga, Joyceline Cuenco, Kei Sakamoto, Carol MacKintosh, Ian G. Ganley

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引用次数: 0

摘要

有丝分裂能降解受损的线粒体，但我们在此表明，它也能以功能线粒体为目标。后一种情况发生在程序性有丝分裂过程中，涉及有丝分裂受体 NIX 和 BNIP3。虽然能量感应蛋白激酶 AMP 激活蛋白激酶（AMPK）能影响受损诱导的有丝分裂，但它在程序性有丝分裂中的作用还不清楚。我们发现，AMPK通过ULK1在两个位点（Ser556和另一个已确定的位点Ser694）的磷酸化，触发14-3-3介导的ULK1固着，从而直接抑制NIX依赖的有丝分裂。相比之下，AMPK 的激活会增加 Parkin 的磷酸化并提高去极化诱导的有丝分裂率，而与 ULK1 无关。我们利用有丝分裂-QC 小鼠模型表明，这种情况既发生在培养细胞中，也发生在体内组织中。我们的研究揭示了一种机制，即 AMPK 激活会下调功能线粒体的有丝分裂，但会增强功能障碍/受损线粒体的有丝分裂。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Opposing roles for AMPK in regulating distinct mitophagy pathways

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Opposing roles for AMPK in regulating distinct mitophagy pathways

Mitophagy degrades damaged mitochondria, but we show here that it can also target functional mitochondria. This latter scenario occurs during programmed mitophagy and involves the mitophagy receptors NIX and BNIP3. Although AMP-activated protein kinase (AMPK), the energy-sensing protein kinase, can influence damaged-induced mitophagy, its role in programmed mitophagy is unclear. We found that AMPK directly inhibits NIX-dependent mitophagy by triggering 14-3-3-mediated sequestration of ULK1, via ULK1 phosphorylation at two sites: Ser556 and an additional identified site, Ser694. By contrast, AMPK activation increases Parkin phosphorylation and enhances the rate of depolarization-induced mitophagy, independently of ULK1. We show that this happens both in cultured cells and tissues in vivo, using the mito-QC mouse model. Our work unveils a mechanism whereby AMPK activation downregulates mitophagy of functional mitochondria but enhances that of dysfunctional/damaged ones.

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.