8.A.185. The Mitolamban (Mtlbn) Family
Emerging evidence indicates that a subset of RNA molecules annotated as noncoding contain short open reading frames that code for small functional proteins called microproteins, which have largely been overlooked due to their small sizes. To search for cardiac-expressed microproteins, Makarewich et al. 2022 used a comparative genomics approach and identified mitolamban (Mtlbn) as a highly conserved 47-amino acid transmembrane protein that is abundantly expressed in the heart. Mtlbn localizes specifically to the inner mitochondrial membrane where it interacts with subunits of complex III of the electron transport chain and with mitochondrial respiratory supercomplexes. Genetic deletion of Mtlbn in mice altered complex III assembly dynamics and reduced complex III activity. Unbiased metabolomic analysis of heart tissue from Mtlbn knockout mice further revealed an altered metabolite profile consistent with deficiencies in complex III activity. Cardiac-specific Mtlbn overexpression in transgenic (TG) mice induced cardiomyopathy with histological, biochemical, and ultrastructural pathologic features that contribute to premature death. Metabolomic analysis and biochemical studies indicated that hearts from Mtlbn TG mice exhibited increased oxidative stress and mitochondrial dysfunction. These findings reveal Mtlbn as a cardiac-expressed inner mitochondrial membrane microprotein that contributes to mitochondrial electron transport chain activity through direct association with complex III and the regulation of its assembly and function (Makarewich et al. 2022).
References:
Short transmembrane mitochondrial protein 1, STMP1 or mitolamban, a precursor of 47 aas and 1 TMS. This protein is a regulator of mitochondrial electron transfer Complex III. See family description for details (Makarewich et al. 2022).
STMP1 of Homo sapiens
Short transmembrane mitochondrial protein 1, STMP1, of 56 aas and 1 N-terminal TMS.
STMP1 of Medicago truncatula (barrel medic)
SLC35A4 upstream open reading frame protein-like of 104 aas and 1 C-terminal TMS.
SLC35A4 of Electrophorus electricus
Uncharacterized protein of 67 aas and 1 TMS/
UC protein of Dinothrombium tinctorium
Uncharacterized protein of 47 aas and 1 N-terminal TMS.
UCP of Cotesia congregata
Uncharacterized protein of 43 aas and 1 TMS.
UP of Heterostelium album
SLC35A4-MP (microprotein) of 103 aas and 1 TMS. It is an inner mitochondrial membrane microprotein from the SLC35A4 upstream ORF, and it regulates cellular metabolism (Rocha et al. 2024). Upstream ORFs (uORFs) are cis-acting elements that can regulate the translation of downstream ORFs by suppressing downstream translation under basal conditions and, in some cases, increasing downstream translation under stress conditions. Methods have identified uORFs in the 5'-UTRs of approximately half of all mouse and human transcripts. Because the prevailing dogma was that eukaryotic mRNAs produce a single functional protein, the peptides or microproteins, encoded by uORFs were rarely studied. We hypothesized that a uORF in the SLC35A4 mRNA is producing a functional microprotein (SLC35A4-MP) because of its conserved amino acid sequence. The IMM contains the protein machinery crucial for cellular respiration and ATP generation, and loss of function studies with SLC35A4-MP significantly diminish maximal cellular respiration, indicating a vital role for this microprotein in cellular metabolism. The findings add SLC35A4-MP to the growing list of functional microproteins (Rocha et al. 2024).
SLC35A4-MP of Homo sapiens