University thesis:
Dissertation, Universität Freiburg, 2019
Footnote:
Description:
Abstract: Autophagy is a cellular recycling process that is essential for the breakdown of cytoplasmic material. Entire organelles including heavily damaged mitochondria can be disposed of via autophagy (mitophagy) to ensure mitochondrial quality and prevent cellular damage via reactive oxygen species (ROS). The mechanistic target of rapamycin (mTOR) represents the enzymatic core of two structurally distinct complexes. While mTOR complex 1 is a well-established regulator of growth and a potent inhibitor of autophagy, mTOR complex 2 regulates migration and survival, but its function in autophagy regulation remains controversial. <br>In the present study, it is described that C. elegans mTOR complex 2 depletion potently induces autophagy and mitophagy via the serum- and glucocorticoid inducible kinase 1 (SGK-1). Importantly, this function is shown to be independent of DAF-16/FoxO, while activation of SGK-1 by the insulin-like signaling component 3-phosphoinositide-dependent protein kinase 1 (PDK-1) is found to be necessary. Induced autophagy/mitophagy caused by loss of mTOR complex 2/ SGK-1 is demonstrated to reduce brood size, delay development and accelerate removal of embryonic paternal mitochondria after fertilization.<br>Furthermore, mitochondrial depolarization in mTOR complex 2 mutants suggests a crucial role of mTOR complex 2 in the regulation of mitochondrial homeostasis. mTOR complex 2 depletion causes a robust increase of mitochondrial, as well as cytosolic ROS. These increased ROS-levels are shown to cause induction of autophagy/mitophagy upon loss of either mTOR complex 2 or SGK-1, as well as the low brood size of sgk-1 mutants. Interestingly, different factors that are known to be regulated by oxidative stress, including AAK-1/-2(AMPK) and HIF-1 are found to act downstream of mTOR complex 2 and SGK-1 in autophagy regulation. <br>Collectively, the findings of this study establish mTOR complex 2 and SGK-1 as a potent inhibitors of autophagy and mitophagy by controlling mitochondrial homeostasis and ROS production in C. elegans