Well-known signaling proteins exert new functions in the nucleus and mitochondria.

One distinguishing feature of eukaryotic cells is their compartmentalization into organelles, which all have a unique structural and functional identity. Some proteins are exclusively localized in a single organelle, whereas others are found in more than one. A few proteins, whose function was thought to be completely understood, were only recently found to be present in the mitochondria. Although these proteins come from diverse functional classes, their common new denominator is the regulation of respiratory chain activity. Therefore, this review focuses on new functions of the Signal Transducer and Activator of Transcription 3, originally described as a transcription factor, the most prominent Src kinase family members, Src, Fyn, and Yes, which were so far known as plasma membrane-associated molecular effectors of a variety of extracellular stimuli, the tyrosine phosphatase Shp-2 previously characterized as a modulator of cytosolic signal transduction involved in cell growth, development, inflammation, and chemotaxis, and Telomerase Reverse Transcriptase, the key enzyme preventing telomere erosion in the nucleus. Their unexpected localization in other organelles and regulation of mitochondrial and/or nuclear functions by them adds a new layer of regulatory complexity. This extends the flexibility to cope with changing environmental demands using a limited number of genes and proteins.