Figure 9.

Double-SCR of MTCH2 mRNA regulates cellular level of MTCH2 protein and mitochondrial membrane potential. Mammalian MTCH2 mRNA has three evolutionarily conserved stop codons. This mRNA can generate three isoforms depending on the position of translation termination. Translation termination at the first stop codon results in the canonical isoform MTCH2. Read-through across the first stop codon and termination at the second stop codon results in an isoform with 11 extra amino acids at the C terminus (termed MTCH2x). Read-through across the first and the second stop codons (double-stop codon read-through), and termination at the third stop codon results in an isoform with 36 extra amino acids at the C terminus (termed MTCH2xx). MTCH2 and MTCH2x localize to mitochondria. However, MTCH2xx is predominantly cytoplasmic. This mislocalization and the unique C terminus makes this isoform susceptible for proteasomal degradation. Thus, double-stop codon read-through negatively regulates the level of MTCH2 available in the cell, which is critical for the maintenance of physiological level of mitochondrial membrane potential. In the absence of double-SCR, as seen in read-through deficient (ΔRT^MTCH2) cells, MTCH2 level increases and the mitochondrial membrane potential decreases.