# SEA and GATOR 10 Years Later
## 6 SEA and GATOR Functions beyond Nutrient Responding
### Regulation of Mitochondrial Biogenesis and Quality Control  
The mTORC1 pathway plays an essential role in mitochondrial biogenesis, mitochondrial genome repair, the phosphorylation of mitochondrial proteins and the regulation of mitophagy, the selective degradation of mitochondria by autophagy. As a central controller of the mTORC1 pathway, SEA/GATOR is also involved in the regulation of mitochondria function and quality control (Figure 4, Figure 5). The analysis of synthetic genetic interactions in _S. cerevisiae_ revealed already in 2011 that SEA genes interact with many mitochondrial genes, with Npr2 located close to the mitochondrial gene cluster [3; 143; 142]. About 20% of proteins that co-precipitate with SEA components are mitochondrial proteins [13; 135] and, inversely, enriched mitochondrial fractions contain SEA proteins [137]. Both C-terminal GFP tagged Iml1/Sea1 and Sea4 can be localized to the mitochondria [135]. Moreover, treatment with rapamycin significantly increases the amount of cells with cytoplasmic and mitochondrial localizations of Iml1/Sea1, although a fraction of Iml1/Sea1 can still be observed at the vacuole [138]. Similarly, in HEK 293T cells NPRL2 can be localized to the mitochondria and many mitochondrial proteins can be found in the proteome of NPRL2 and NPRL3 [54]. Recently, SESTRIN2, which interacts with GATOR2 during leucine starvation (see above), was also found to be localized to mitochondria and silencing of GATOR2 genes considerably reduced the mitochondrial pool of SESTRIN2 [144]. Finally, Sec13 was shown to be interacting with mitochondrial antiviral signal protein (MAVS, also known as VISA) [145; 146]. MAVS is localized on the outer membrane of mitochondria, with a small proportion present at mitochondria-associated membranes (MAMs). Sec13 overexpression increases MAVS aggregation and facilitates interferon \(\beta\) production, while low levels of Sec13 result in a weaker host antiviral immune response. Currently, it is not clear whether other proteins from nuclear pore complex or COPII or GATOR2 are also involved in these interactions. The deletion of SEA/GATOR components affects mitochondria functions. The total abundance of SEA proteins is increased during respiratory growth and decreased upon nitrogen starvation, _sea2_ deletion impairs respiration capacity in _S. cerevisiae_[147]. _npr2\(\Delta\)_ cells have defective mitochondrial-housed metabolic pathways, such as synthesis of amino acids, and an impaired tricarboxylic acid (TCA) cycle activity. _npr2_-deficient cells showed decreased pools of nitrogen-containing intermediates of the TCA cycle and nucleotides. Yet, _npr2\(\Delta\)_ yeast use TCA cycle intermediates for replenishment of biosynthetic pathways to sustain the hypermetabolic state due to mTOR1 constant activation, suggesting a role of SEACIT in the regulation of cataplerotic reactions of the TCA cycle depending on the amino  
Figure 5: Multiple functions of the SEA/GATOR complex. acid and nitrogen status of the cell [148]. This was later supported by another study that demonstrated that skeletal-muscle-specific NPRL2 loss in mice promoted aerobic glycolysis by altering the tuning between the amino acid sensing pathway and TCA cycle function. NPRL2-mKO mice also had less oxidative muscle fibers and more glycolytic muscle fibers, a hallmark of aerobic glycolysis, which highlights the functional role of NPRL2 in vivo in the regulation of glucose entry into the TCA cycle [149]. The function of GATOR1 proteins in mitochondrial health seems not to be limited to NPRL2. A heterozygous mutation in the CTD domain of DEPDC5 gene found in an autistic child was correlated with a significant decrease in mitochondrial complex IV activity and decrease in the overall oxygen consumption rate in peripheral blood mononuclear cells. Therefore, this variant of DEPDC5 can be directly related to an altered mitochondrial function in autistic disease [150].