SIRT4 is the last puzzle of mitochondrial sirtuins.

Sirtuins are recently redefined as a family of nicotinamide adenine dinucleotide (NAD)-dependent deacylases. Sirtuins in mammals including human have seven members, which are SIRT1-7. Compared to other sirtuin members, not much study is focused on mitochondrial sirtuins (SIRT3-5). In mitochondrial sirtuins, SIRT4 was the last of less well-understood mitochondrial sirtuins especially for its robust enzymatic activity. This makes SIRT4 become the last puzzle of mitochondrial sirtuins, and thus brings some obstacles for studying SIRT4 biological functions or developing SIRT4 modulators. In this review, we will summarize and discuss the current findings for substrates, biological functions and possible enzymatic activities of SIRT4. The purpose of this review is to facilitate in discovering the robust enzymatic activity of SIRT4 and eventually finish this last puzzle of mitochondrial sirtuins.