Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA; Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Dev Cell. 2019 Mar 11;48(5):685-696.e5. doi: 10.1016/j.devcel.2018.12.022. Epub 2019 Jan 31.
Lysosomes and mitochondria are both crucial cellular organelles for metabolic homeostasis and organism health. However, mechanisms linking their metabolic activities to promote organism longevity remain poorly understood. We discovered that the induction of specific lysosomal signaling mediated by a LIPL-4 lysosomal acid lipase and its lipid chaperone LBP-8 increases mitochondrial ß-oxidation to reduce lipid storage and promote longevity in Caenorhabditis elegans. We further discovered that increased mitochondrial ß-oxidation reduces mitochondrial electron transport chain complex II activity, contributing to the induction of reactive oxygen species in mitochondria (mtROS) and the longevity effect conferred by LIPL-4-LBP-8 signaling. Moreover, by activating the JUN-1 transcription factor downstream of mtROS, the LIPL-4-LBP-8 signaling pathway induces antioxidant targets and oxidative stress tolerance. Together, these results reveal regulatory mechanisms by which lysosomal signaling triggers adjustments in mitochondrial activity and suggest the significance of these metabolic adjustments for improving metabolic fitness, redox homeostasis, and longevity.
溶酶体和线粒体都是细胞代谢稳态和机体健康的关键细胞器。然而，将它们的代谢活动联系起来以促进机体长寿的机制仍知之甚少。我们发现，由溶酶体酸性脂肪酶 LIPL-4 和其脂质伴侣 LBP-8 介导的特定溶酶体信号的诱导增加了线粒体的β-氧化，从而减少脂质储存并促进秀丽隐杆线虫的长寿。我们进一步发现，增加的线粒体β-氧化降低了线粒体电子传递链复合物 II 的活性，导致线粒体中活性氧物质（mtROS）的产生和由 LIPL-4-LBP-8 信号诱导的长寿效应。此外，通过激活 mtROS 下游的 JUN-1 转录因子，LIPL-4-LBP-8 信号通路诱导抗氧化靶标和氧化应激耐受。总之，这些结果揭示了溶酶体信号触发线粒体活性调整的调节机制，并表明这些代谢调整对于改善代谢适应性、氧化还原稳态和长寿的重要性。
