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Cell Syst. 2017 Dec 27;5(6):564-577.e12. doi: 10.1016/j.cels.2017.10.010. Epub 2017 Nov 8.

A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling.

Author information

1
Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada.
2
Department of Computer Science, University of Regina, Regina, SK S4S 0A2, Canada.
3
The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
4
Department of Medicine, Harvard Medical School and Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
5
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.
6
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
7
Hospital for Sick Children, 21-9830 PGCRL, 686 Bay Street, Toronto, ON M5G 0A4, Canada.
8
Department of Medicine, Regina Qu'Appelle Health Region, Regina, SK S4P 0W5, Canada.
9
Department of Science and High Technology, Center of Neuroscience, University of Insubria, Via Alberto da Giussano 12, Busto Arsizio I-21052, Italy.
10
Molecular Neurogenetics Unit, IRCCS Foundation C. Besta Neurological Institute, via L. Temolo, 4, 20126 Milan, Italy.
11
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
12
Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, Canada. Electronic address: mohan.babu@uregina.ca.

Abstract

Mitochondrial protein (MP) dysfunction has been linked to neurodegenerative disorders (NDs); however, the discovery of the molecular mechanisms underlying NDs has been impeded by the limited characterization of interactions governing MP function. Here, using mass spectrometry (MS)-based analysis of 210 affinity-purified mitochondrial (mt) fractions isolated from 27 epitope-tagged human ND-linked MPs in HEK293 cells, we report a high-confidence MP network including 1,964 interactions among 772 proteins (>90% previously unreported). Nearly three-fourths of these interactions were confirmed in mouse brain and multiple human differentiated neuronal cell lines by primary antibody immunoprecipitation and MS, with many linked to NDs and autism. We show that the SOD1-PRDX5 interaction, critical for mt redox homeostasis, can be perturbed by amyotrophic lateral sclerosis-linked SOD1 allelic variants and establish a functional role for ND-linked factors coupled with IκBɛ in NF-κB activation. Our results identify mechanisms for ND-linked MPs and expand the human mt interaction landscape.

PMID:
29128334
PMCID:
PMC5746455
DOI:
10.1016/j.cels.2017.10.010
[Indexed for MEDLINE]
Free PMC Article

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