C11orf83, a Mitochondrial Cardiolipin-Binding Protein Involved in bc₁ Complex Assembly and Supercomplex Stabilization

Abstract

Mammalian mitochondria may contain up to 1,500 different proteins, and many of them have neither been confidently identified nor characterized. In this study, we demonstrated that C11orf83, which was lacking experimental characterization, is a mitochondrial inner membrane protein facing the intermembrane space. This protein is specifically associated with the bc₁ complex of the electron transport chain and involved in the early stages of its assembly by stabilizing the bc₁ core complex. C11orf83 displays some overlapping functions with Cbp4p, a yeast bc₁ complex assembly factor. Therefore, we suggest that C11orf83, now called UQCC3, is the functional human equivalent of Cbp4p. In addition, C11orf83 depletion in HeLa cells caused abnormal crista morphology, higher sensitivity to apoptosis, a decreased ATP level due to impaired respiration and subtle, but significant, changes in cardiolipin composition. We showed that C11orf83 binds to cardiolipin by its α-helices 2 and 3 and is involved in the stabilization of bc₁ complex-containing supercomplexes, especially the III₂/IV supercomplex. We also demonstrated that the OMA1 metalloprotease cleaves C11orf83 in response to mitochondrial depolarization, suggesting a role in the selection of cells with damaged mitochondria for their subsequent elimination by apoptosis, as previously described for OPA1.

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.01047-14.

ACKNOWLEDGMENTS

We thank Denis Martinvalet, Oliver Hartley, Maureen Deehan, Paula Duek, Rachel Porcelli, Marianne Paolini-Bertrand, and Irène Rossitto-Borlat for comments and suggestions, review of the manuscript, and technical assistance, and we thank Mathias Uhlen (Human Protein Atlas, Sweden) for providing a number of rabbit polyclonal antibodies against mitochondrial proteins. We thank the PFMU at the Faculty of Medicine, Geneva, Switzerland, for access to transmission electron microscopy equipment and M. A. T. Vervaart, Laboratory Genetic Diseases, Amsterdam, The Netherlands, for performing the CL MS analysis.

This work was supported by the Faculty of Medicine of the University of Geneva, the Swiss National Science Foundation (grant no. 310030-152618 and CRSII3-141798 to M.F.), and the Ernst and Lucie Schmidheiny Foundation (grant to M.D.).