Micropeptides

Micropeptides are short peptides, typically under 100 amino acids, encoded by small open reading frames (sORFs) that can reside within messenger RNAs, long noncoding RNAs, or other RNA species. Unlike conventional proteins annotated long ago, micropeptides have only recently been recognized as functional regulators in a variety of tissues. Their small size makes them challenging to detect, and many were overlooked by standard gene annotation.

Advances in ribosome profiling (Ribo-seq) and high-resolution mass spectrometry have revealed a large class of translated sORFs. Experimental approaches include CRISPR-based perturbations and overexpression studies to determine function. Because many micropeptide genes are embedded in noncoding transcripts or overlapping canonical coding regions, careful validation is required.

Micropeptides participate in diverse processes: regulation of metabolism, development, and muscle physiology; mitochondrial function; secreted signaling. Notable examples include DWORF, a 34 aa peptide that enhances SERCA calcium uptake in cardiac muscle; myoregulin and sarcolipin, ~46 and ~31 aa, which inhibit SERCA; humanin, a 24 aa mitochondrial-encoded peptide with cytoprotective effects; and developmental peptides such as Toddler.

Most micropeptides arise from sORFs within mRNAs or lncRNAs and sometimes from small regions within coding sequences. Their discovery has prompted revisions to genome annotation and an expanding view of the coding potential of the transcriptome. Therapeutically, micropeptides are explored as targets or catalysts for treating muscular, metabolic, and degenerative diseases.