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).



Makarewich, C.A., A.Z. Munir, S. Bezprozvannaya, A.M. Gibson, S. Young Kim, M.S. Martin-Sandoval, T.P. Mathews, L.I. Szweda, R. Bassel-Duby, and E.N. Olson. (2022). The cardiac-enriched microprotein mitolamban regulates mitochondrial respiratory complex assembly and function in mice. Proc. Natl. Acad. Sci. USA 119:.


TC#NameOrganismal TypeExample

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