Institute of Cellular Biology, University Medical Center Goettingen, Goettingen, Germany.
Doctoral Program on Molecular Medicine, University of Goettingen, Goettingen, Germany.
Sci Rep. 2017 Mar 27;7:45076. doi: 10.1038/srep45076.
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.
线粒体是细胞信号的关键平台，影响细胞增殖、分化和死亡等基本过程。然而，线粒体信号如何影响其他细胞器，特别是溶酶体，目前还不清楚。在这里，我们证明线粒体呼吸链 (RC) 的损伤会引发一种应激信号通路，通过小眼畸形转录因子家族调节溶酶体发生。有趣的是，线粒体应激对溶酶体发生的影响取决于应激引发的时间框架：虽然用鱼藤酮抑制 RC 或用 CCCP 解偶联最初会触发溶酶体发生，但几小时后效果达到峰值，然后恢复到基线。用鱼藤酮长期处理或成纤维细胞和小鼠模型中的患者突变长期抑制 RC 会抑制溶酶体发生。短期线粒体应激诱导的溶酶体发生依赖于 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功能障碍的后果，特别是在线粒体疾病的背景下，是至关重要的。
