Clues of in vivo nuclear gene regulation by mitochondrial short non-coding RNAs

Gene expression involves multiple processes, from transcription to translation to the mature, functional peptide, and it is regulated at multiple levels. Small RNA molecules are known to bind RNA messengers affecting their fate in the cytoplasm (a process generically termed 'RNA interference'). Such small regulatory RNAs are well-known to be originated from the nuclear genome, while the role of mitochondrial genome in RNA interference was largely overlooked. However, evidence is growing that mitochondrial DNA does provide the cell a source of interfering RNAs. Small mitochondrial highly transcribed RNAs (smithRNAs) have been proposed to be transcribed from the mitochondrion and predicted to regulate nuclear genes. Here, for the first time, we show in vivo clues of the activity of two smithRNAs in the Manila clam, Ruditapes philippinarum. Moreover, we show that smithRNAs are present and can be annotated in representatives of the three main bilaterian lineages; in some cases, they were already described and assigned to a small RNA category (e.g., piRNAs) given their biogenesis, while in other cases their biogenesis remains unclear. If mitochondria may affect nuclear gene expression through RNA interference, this opens a plethora of new possibilities for them to interact with the nucleus and makes metazoan mitochondrial DNA a much more complex genome than previously thought.