The Parkinson's disease–linked proteins Fbxo7 and Parkin interact to mediate mitophagy


Compelling evidence indicates that two autosomal recessive Parkinson's disease genes, PINK1 (PARK6) and Parkin (PARK2), cooperate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain–containing protein Fbxo7 (encoded by PARK15) also cause early-onset autosomal recessive Parkinson's disease, by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and acts in Parkin-mediated mitophagy. Cells with reduced Fbxo7 expression showed deficiencies in translocation of Parkin to mitochondria, ubiquitination of mitofusin 1 and mitophagy. In Drosophila, ectopic overexpression of Fbxo7 rescued loss of Parkin, supporting a functional relationship between the two proteins. Parkinson's disease–causing mutations in Fbxo7 interfered with this process, emphasizing the importance of mitochondrial dysfunction in Parkinson's disease pathogenesis.

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Figure 1: The N-terminal Ubl domain of Fbxo7 interacts directly with Parkin.
Figure 2: Fbxo7 participates in CCCP-induced accumulation of Parkin at the mitochondria.
Figure 3: Expression of Fbxo7 rescues parkin mutant phenotypes.
Figure 4: PINK1 interacts directly with the amino terminus of Fbxo7.
Figure 5: Functional interaction of Fbxo7 with PINK1.
Figure 6: Fbxo7 promotes Mfn1 ubiquitination and restores Mfn levels and mitochondrial morphology in Parkin- but not PINK1-deficient cells.
Figure 7: Fbxo7 is important for mitophagy.


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We would like to thank M. Mehrabian and E. Elahi for obtaining patient biopsies, H. Ardley (Leeds Institute of Molecular Medicine) for donating the Flag-Parkin construct and cell line, K. Holmström and A. Isaacs for discussions and M. Gegg for technical advice. We thank C. Hill for technical assistance within the University of Sheffield Electron Microscopy Facility. We thank the H. Steller (Rockefeller University) laboratory for kind provision of the ntc mutant lines. The work was funded by a Wellcome/Medical Research Council (MRC) Parkinson's Disease Consortium grant to the University College London Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee (grant number WT089698), an MRC Career Development Award (G0700183; H.P.-F.), the MEFOPA project funded through the European Union FP7 research program (A.J.W.), and an ERC Starting Grant (no. 309742; A.J.W.). This research was supported by the UK National Institute for Health Research University College London Hospitals Biomedical Research Centre. V.S.B. is funded by the MRC Doctoral Training Account. D.E.N. is funded by the Biotechnology and Biological Sciences Research Council (BB/F012764/1; BB/J007846/1). The Wellcome Trust is acknowledged for support of the Sheffield Light Microscopy Facility (GR077544AIA). The MRC Centre for Developmental and Biomedical Genetics is supported by grant G070091.

Author information

H.P.-F., H.L. and A.J.W. conceived the study. V.S.B., D.E.N., A.S.-M., A.J.W., H.L. and H.P.-F. designed and performed experiments. M.D.-C., R.M.I., J.H.P. and S.J.R. performed experiments. H.H., P.A.L. and S.W. obtained and cultured the patient fibroblasts. P.A.L., A.Y.A., J.H. and N.W.W. contributed to the design of the study. V.S.B., D.E.N., A.S.-M., H.P.-F., A.J.W. and H.L. wrote the manuscript.

Correspondence to Alexander J Whitworth or Heike Laman or Helene Plun-Favreau.

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Burchell, V., Nelson, D., Sanchez-Martinez, A. et al. The Parkinson's disease–linked proteins Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci 16, 1257–1265 (2013).

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