Roles of Mitochondrial Amino Acid Sensing in the Pathologies of Fatty Liver

 

Abstract

Insufficient protein intake could cause a variety of systemic diseases, ranging from sarcopenia to kwashiorkor, depending on its severity. Accumulating evidence suggests that under protein malnutrition multiple organs crosstalk to one another to form systemic pathophysiological responses, while their detailed mechanisms remain to be fully elucidated. Here we show that the suppression of liver histidyl-tRNA synthetase Hars2, a model mimicking histidine insufficiency specifically in mitochondria of liver, leads to strong mitochondrial stress responses in the liver. The induction of mitochondrial stress responses was mediated by a cellular amino acid sensor GCN2 kinase. Interestingly, the suppression of other mitochondrial aminoacyl tRNA synthetases, such as that of alanyl tRNA synthetase 2 (Aars2) or leucyl tRNA synthetase 2 (Lars2), failed to elicit the mitochondrial stress responses. These data suggest that insufficiency of histidine alone in mitochondrial was enough to induce whole-cell responses as seen under global amino acid starvation, and indicate the unique roles of histidine therein, as a representative amino acid for the mitochondria to sense the global amino acid availability. The mitochondrial stress responses induced by liver Hars2 suppression included the upregulation of FGF21 and GDF15, both of which are known to suppress food intake, implying a vicious cycle that could potentially exacerbate malnutrition under insufficient protein intake. On the other hand, liver Hars2 suppression or treatment of hepatocytes with mitochondrial stressors led to an induction of PPARγ, one of the master regulators of lipid metabolism that promotes liver steatosis as seen in kwashiorkor. These data unveil the previously uncharacterized mechanisms of cellular amino acid sensing and resultant systemic responses, aiding the understanding as well as the therapeutic developments of protein malnutrition-related pathologies.

 

Reference

Matsushita M, Awazawa M et al, An antisense transcript transcribed from Irs2 locus contributes to the pathogenesis of hepatic steatosis in insulin resistance. Cell Chem Biol. 29(4): 680-689, 2022