A short C‐terminal tail prevents mis‐targeting of hydrophobic mitochondrial membrane proteins to the ER

Sdh3/Shh3, a subunit of mitochondrial succinate dehydrogenase, contains transmembrane domains with a hydrophobicity comparable to that of endoplasmic reticulum (ER) proteins. Here, we show that a C‐terminal reporter fusion to Sdh3/Shh3 results in partial mis‐targeting of the protein to the ER. This mis‐targeting is mediated by the signal recognition particle (SRP) and depends on the length of the C‐terminal tail. These results imply that if nuclear‐encoded mitochondrial proteins contain strongly hydrophobic transmembrane domains and a long C‐terminal tail, they have the potential to be recognized by SRP and mis‐targeted to the ER.