Peptides derived from small mitochondrial open reading frames: Genomic, biological, and therapeutic implications

Abstract Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins that modify cell metabolism. To date, eight MDPs have been characterized (e.g., humanin, MOTS-c, SHLPs1-6) and attenuate disease pathology, including Alzheimer's disease, prostate cancer, macular degeneration, cardiovascular disease, and diabetes. Human genetic variation in these MDPs is underexplored, but two polymorphisms in humanin and MOTS-c associate with cognitive decline and diabetes, respectively, suggesting a precise role for MDPs in disease-modification. There could be hundreds of additional MDPs that have yet to be discovered. Altogether, MDPs could explain unanswered biological and metabolic questions and are part of a growing field of novel microproteins encoded by small open reading frames. In this review, the current state of MDPs are summarized with an emphasis on biological and therapeutic implications.