Ancestral sequence reconstruction of the Mic60 Mitofilin domain reveals residues supporting respiration in yeast
In eukaryotes, cellular respiration takes place in the cristae of mitochondria. The mitochondrial inner membrane protein Mic60, a core component of the mitochondrial contact site and cristae organizing system, is crucial for the organization and stabilization of crista junctions and its associated functions. While the C-terminal Mitofilin domain of Mic60 is necessary for cellular respiration, the sequence determinants for this function have remained unclear. Here, we used ancestral sequence reconstruction to generate Mitofilin ancestors up to and including the last opisthokont common ancestor (LOCA). We found that yeast-lineage derived Mitofilin ancestors as far back as the LOCA rescue respiration. By comparing Mitofilin ancestors, we identified four residues sufficient to explain the respiratory difference between yeast- and animal-derived Mitofilin ancestors. Our results provide a foundation for investigating the conservation of Mic60-mediated cristae junction interactions.
Authors
- Mary‐Margaret Keating
- Tristan A. Bell (ORCID: https://orcid.org/0000-0002-3668-8412)
- Anja E. H. Nordstrom
- Margaret Coughlin
- Della Syau (ORCID: https://orcid.org/0000-0002-8192-2220)
- Yi‐Ting Liao (ORCID: https://orcid.org/0000-0001-5050-7481)
- Maria Ericsson (ORCID: https://orcid.org/0000-0002-4563-3683)
- Tran H. Nguyen (ORCID: https://orcid.org/0009-0007-6084-3017)
- Luke H. Chao (ORCID: https://orcid.org/0000-0002-4849-4148)
- Friederike M. C. Benning (ORCID: https://orcid.org/0000-0002-1002-4204)
- Corrie J.B. daCosta (ORCID: https://orcid.org/0000-0002-9546-5331)
- Louise B. Connell (ORCID: https://orcid.org/0000-0002-3276-8626)
Institutions
- Boston University (US)
- Harvard University (US)
- University of Ottawa (CA)
- Massachusetts General Hospital (US)
Publication Details
- Journal
- Protein Science
- Published
- 2025-06-22
- DOI
- https://doi.org/10.1002/pro.70207
- Citations
- 3
- Primary Topic
- Genetics, Aging, and Longevity in Model Organisms
- Type
- article
- Field-Weighted Citation Impact
- 2.86
Funders
- Simons Foundation
- Gordon and Betty Moore Foundation
- Helen Hay Whitney Foundation
- Canada Foundation for Innovation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- National Institutes of Health
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada