Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.
Acute and chronic mitochondrial respiratory chain deficiency differentially regulate lysosomal biogenesis.
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DOI：
10.1038/srep45076
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发表时间：
2017-03-27
影响因子：
4.6
通讯作者：
Raimundo N
中科院分区：
文献类型：
--
作者：
Fernández-Mosquera L;Diogo CV;Yambire KF;Santos GL;Luna Sánchez M;Bénit P;Rustin P;Lopez LC;Milosevic I;Raimundo N
线粒体是关键的细胞信号平台，影响细胞的增殖、分化和死亡等基本过程。然而，目前还不清楚线粒体信号如何影响其他细胞器，特别是溶酶体。在这里，我们证明了线粒体呼吸链(RC)的损伤诱导了一条应激信号通路，该通路通过小巨噬细胞转录因子家族来调节溶酶体的生物发生。有趣的是，线粒体应激对溶酶体生物发生的影响取决于应激的时间框架：当RC被鱼藤酮抑制或与CCCP解偶联时，最初触发溶酶体生物发生，几小时后影响达到峰值，然后回到基线。通过鱼藤酮长期治疗的RC抑制，或在成纤维细胞和小鼠模型中的患者突变导致溶酶体生物发生的抑制。短期线粒体应激诱导溶酶体的生物发生依赖于TFEB和MITF，需要AMPK信号，而不依赖于钙调神经磷酸酶信号。这些结果揭示了线粒体信号如何影响溶酶体的综合观点，这对于充分理解线粒体故障的后果是必不可少的，特别是在线粒体疾病的背景下。
Mitochondria are key cellular signaling platforms, affecting fundamental processes such as cell proliferation, differentiation and death. However, it remains unclear how mitochondrial signaling affects other organelles, particularly lysosomes. Here, we demonstrate that mitochondrial respiratory chain (RC) impairments elicit a stress signaling pathway that regulates lysosomal biogenesis via the microphtalmia transcription factor family. Interestingly, the effect of mitochondrial stress over lysosomal biogenesis depends on the timeframe of the stress elicited: while RC inhibition with rotenone or uncoupling with CCCP initially triggers lysosomal biogenesis, the effect peaks after few hours and returns to baseline. Long-term RC inhibition by long-term treatment with rotenone, or patient mutations in fibroblasts and in a mouse model result in repression of lysosomal biogenesis. The induction of lysosomal biogenesis by short-term mitochondrial stress is dependent on TFEB and MITF, requires AMPK signaling and is independent of calcineurin signaling. These results reveal an integrated view of how mitochondrial signaling affects lysosomes, which is essential to fully comprehend the consequences of mitochondrial malfunction, particularly in the context of mitochondrial diseases.