National Academy of Sciences, Proceedings of the National Academy of Sciences, 25(112), p. 7713-7718, 2015
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Significance Mitochondria contain several hundreds of proteins. The mitochondrial content is regulated by the uptake and degradation of proteins. Stabilization of protein structure by disulfide bonds was proposed to drive protein accumulation in the intermembrane space of mitochondria. However, it remained unknown if structural alterations could lead to protein escape through the physiological barrier formed by the outer mitochondrial membrane. In this work, we present evidence for size-dependent retrograde movement of mitochondrial proteins to the cytosol. We identify the translocase of the outer mitochondrial membrane channel protein Tom40 as an exit route. Our results indicate that the retro-translocation serves as an important surveillance mechanism that regulates the abundance of intermembrane space proteins in response to changes in cellular physiology.