Rheb and mammalian target of rapamycin in mitochondrial homoeostasis

Abstract

Mitochondrial dysfunction has been associated with various diseases, such as cancer, myopathies, neurodegeneration and obesity. Mitochondrial homoeostasis is achieved by mechanisms that adapt the number of mitochondria to that required for energy production and for the supply of metabolic intermediates necessary to sustain cell growth. Simultaneously, mitochondrial quality control mechanisms are in place to remove malfunctioning mitochondria. In the cytoplasm, the protein complex mTORC1 couples growth-promoting signals with anabolic processes, in which mitochondria play an essential role. Here, we review the involvement of mTORC1 and Rheb in mitochondrial homoeostasis. The regulatory processes downstream of mTORC1 affect the glycolytic flux and the rate of mitophagy, and include regulation of the transcription factors HIF1α and YY1/PGC-1α. We also discuss how mitochondrial function feeds back on mTORC1 via reactive oxygen species signalling to adapt metabolic processes, and highlight how mTORC1 signalling is integrated with the unfolded protein response in mitochondria, which in Caenorhabditis elegans is mediated via transcription factors such as DVE-1/UBL-5 and ATFS-1.

ATM directs DNA damage responses and proteostasis via genetically separable pathways

“…The amount of lysosome-dependent mitochondrial turnover can thus be measured by the pH of the mitochondria-targeted probe. We tested the mKeima probe using the mTOR inhibitor rapamycin, which induces mitophagy (48), in comparison to wortmannin, which blocks mitophagy through inhibition of PI3 kinase (49, 50). In wild-type U2OS cells, rapamycin increased the fold change in mKeima emission whereas wortmannin reduced the ratio, as expected (Fig.…”

mTOR in Brain Physiology and Pathologies

“…Rheb contains a CaaX box at its COOH terminus, which is farnesylated. Thus Rheb is associated with intracellular membranes such as Golgi (34), late endosomes (79), lysosomes (207,253), peroxisomes (24), and mitochondria (FIGURE 3) (88,192). Rheb is also associated with plasma membrane via its physical interaction with plasma membrane receptors such as NMDA (273) and 5-HT 6 receptors (190).…”

“…REDD1 (regulated in development and DNA damage responses 1, also named RTP801), an hypoxia-inducible HIF1␣ target gene, has a crucial role in inhibiting mTORC1 through an unknown mechanism implying activation of TSC2 (FIGURE 5) (148). Exposure of cells to high concentrations of reactive oxygen species (ROS) inhibits mTORC1 activity at the mitochondria and peroxisome level (FIGURE 3), while low ROS levels activate mTORC1 (24,88,159). TSC1/2 interaction with growth arrest and DNA damage protein 34 (GADD34) induces TSC2 dephosphorylation and, consequently, inhibits mTORC1 (108).…”

“…Certain stress conditions, such as hypoxia, activate mitophagy. In addition, damaged mitochondria are selectively degraded under normoxic conditions (88,192). Upon high oxidative phosphorylation activity, Rheb is recruited to the mitochondrial outer membrane to promote mitophagy.…”

Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy

“…Mitochondria also have ubiquitin independent LC3 receptor proteins such as BNIP3, NIX and FUNDC1. 53,54) Non-selective macroautophagy and selective organellophagy can be regulated independently. This allows cells to preserve or remove organelles depending on the demands, regardless of the level of overall autophagic flux.…”