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| Item Type: | Preprint |
|---|---|
| Title: | Topology control by a conserved cysteine pair in the OMM-protein CCDC127 enables MICOS interaction |
| Creators Name: | Zarges, Christine, Schepsky, Pauline, Rothemann, Robin Alexander, Bock-Bierbaum, Tobias, von der Malsburg, Alexander, Baumann, Linda, Trifunovic, Aleksandra, Daumke, Oliver, van der Laan, Martin, von der Malsburg, Karina and Riemer, Jan |
| Abstract: | Mitochondrial disulfide relay substrates beyond the canonical substrates remain incompletely defined. Revisiting the human MIA40 interactome with enhanced depth, we identified CCDC127 as a previously unrecognized substrate candidate. CCDC127 contains a single transmembrane segment and a conserved C-terminal helical bundle domain (CHB). Comprehensive proteomic and biochemical analyses revealed that, contrary to earlier reports, CCDC127 adopts an N(out)–C(in) topology in the outer mitochondrial membrane (OMM) with its CHB residing in the intermembrane space (IMS). CCDC127 undergoes oxidation by the disulfide relay, forming a long-range intramolecular disulfide bond between C174 and C219. Loss of these cysteines disrupts correct OMM insertion, inverts transmembrane topology and triggers proteasome-dependent degradation, establishing the disulfide as a key determinant of CCDC127 maturation. Interactome analyses identified MICOS components— particularly the MIC60/MIC19 module—as major partner proteins required for the stability of large oligomeric CCDC127 complexes. CCDC127 deficiency impaired cellular proliferation, influenced phospholipid levels, and caused grossly altered cristae morphology. Together, CCDC127 emerges as a MICOS-associated OMM protein essential for mitochondrial membrane organization and lipid homeostasis. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2025.12.12.693940 |
| Date: | 15 December 2025 |
| Official Publication: | https://doi.org/10.64898/2025.12.12.693940 |
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