Mechanisms of Megamitochondria Formation in NASH

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Despite being one of the most prevalent metabolic diseases in the United States, nonalcoholic steatohepatitis (NASH) cannot currently be treated by any FDA-approved medicine. To develop effective drugs for this disease, it is urgent and necessary to understand the pathogenic mechanisms of NASH. It has long been a mystery why some NASH patients have extremely large mitochondria, termed megamitochondria, in their hepatocytes. Our preliminary studies have revealed that megamitochondria is crucial factor for the NASH pathogenesis and at least 20% of NASH patients possess megamitochondria in their hepatocytes. Therefore, uncovering the mechanism of megamitochondria formation benefits in finding therapeutic targets for a large portion of patients with NASH. Our study using a diet-induced preclinical NASH mouse model indicated methionine- and choline-deficient (MCD) diet feeding developed megamitochondria in their hepatocytes. Interestingly, however, choline-deficient (CD) diet feeding did not change mitochondrial morphology, suggesting methionine deficiency is the key to megamitochondria formation. Previous studies have shown that methionine is the dietary essential amino acid and its deficiency causes systemic metabolic changes in multiple organs. Methionine is necessary for ribosomal docking and translational initiation because methionine is the start codon. If this amino acid is insufficient, proteolysis is activated to obtain one from existing proteins or polypeptides. Upregulated protein degradation releases a large number of free amino acids that will not be used for protein translation. Because amino acids are primarily degraded in hepatic mitochondria via the TCA cycle and the Urea cycle, excess amino acids are transported to hepatocytes. Given these findings, we hypothesized that the elevation of systemic proteolysis would occur in the MCD diet-induced model, which leads to the amino acid overload of hepatic mitochondria. When methionine deficiency occurs, the skeletal muscles release a great deal of amino acids, due to the fact that 50-75% of our body's proteins exist in skeletal muscles. And the activation of amino acid catabolism due to diet feeding would cause the megamitochondria formation in this model. These hypotheses will be addressed in the experiments with the following Specific Aims: 1) to determine whether skeletal muscle proteolysis is upregulated by methionine deficiency, and 2) to determine the elevated hepatic amino acid catabolism drives the megamitochondria formation. If our hypothesis is correct, it would suggest that the metabolic interaction between skeletal muscles and livers has significant roles in the pathogenesis of megamitochondria-associated NASH. Moreover, it will demonstrate how metabolic changes after amino acid overload affect mitochondrial morphology in hepatocytes. As a result of these findings, new therapeutic strategies with novel targets will be developed to treat patients with NASH.