MTALTCO1: a 259 amino acid long mtDNA-encoded alternative protein that challenges conventional understandings of mitochondrial genomics.

Mitochondrial derived peptides and proteins significantly expand the coding potential of the human mitogenome. Here, we report the discovery of MTALTCO1, a 259 amino acid protein encoded by a mitochondrial alternative open reading frame (mtaltORF) found in the +3 reading frame of the cytochrome oxidase 1 (CO1) gene. Using custom antibodies, we confirmed the mitochondrial expression of MTALTCO1 in human cell lines. Sequence analysis revealed high arginine content and an elevated isoelectric point that were not contingent on CO1's amino acid sequence, suggesting selective pressures acting on this protein. MTALTCO1 displays extensive fusion-fission dynamics at the interspecies level, yet produces a full-length protein throughout human haplogroups. Our findings highlight the importance of identifying novel mtaltORFs in expanding our understanding of the mitochondrial proteome.