Non-canonical ORFs-derived protein products in mitochondria: A multifaceted exploration of their functions in health and disease.

Traditionally, eukaryotic mRNAs were perceived as inherently monocistronic. However, recent insights from ribosome profiling (Ribo-seq) and proteomics studies challenge this paradigm. These investigations reveal that, beyond the currently annotated reference proteins (RefProts), there exist additional proteins known as alternative proteins (AltProts) and small open reading frames derived microproteins encoded in regions of mRNAs previously considered untranslated or in non-coding transcripts. This experimental evidence broadens the spectrum of functional proteins within cells, tissues, and organs, potentially offering crucial insights into biological processes. Notably, a significant proportion of these newly identified AltProts and microproteins demonstrates localization in mitochondria, contributing to the functions of mitochondrial complexes. This review delves into the overlooked realm of the alternative proteome within mitochondria, exploring the role of nuclear or mitochondrial-genome-encoded AltProts and microproteins in physiological and pathological cellular processes.