Fig. 7
From: CO2-sensitive tRNA modification associated with human mitochondrial disease
Metabolism of bicarbonate and t6A37 formation in cytoplasm and mitochondria. CO2 produced by TCA cycle is hydrated to form bicarbonate by carbonic anhydrase 5 (CA5) in mitochondria. In addition, mitochondrial CO2 is exported to cytoplasm and hydrated by carbonic anhydrase 2 (CA2). In hypoxic conditions, carbonic anhydrase 9 (CA9) is overexpressed on the cell surface by HIF-1 pathway. CA9 generates large amounts of bicarbonate outside the cell. Then, cells actively import extracellular bicarbonate to neutralize lactate and prevent acidification. YRDC employs bicarbonate to synthesize TC-AMP, which is used for t6A37 formation on tRNAs mediated by KEOPS complex in cytoplasm and by OSGEPL1 in mitochondria. Hypomodification of t6A37 in two mt-tRNAs in the cells cultured without bicarbonate, as well as from hypoxic solid tumors, indicating codon-specific translational regulation by sensing intracellular bicarbonate
