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 I kappa B epsilon in NF-kappa B activation. Our results identify mechanisms for ND-linked MPs and expand the human mt interaction landscape.

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

Alberio, Tiziana;
2017

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 I kappa B epsilon in NF-kappa B activation. Our results identify mechanisms for ND-linked MPs and expand the human mt interaction landscape.
http://www.journals.elsevier.com/cell-systems/
2734; Histology; Cell Biology
Malty, Ramy H.; Aoki, Hiroyuki; Kumar, Ashwani; Phanse, Sadhna; Amin, Shahreen; Zhang, Qingzhou; Minic, Zoran; Goebels, Florian; Musso, Gabriel; Wu, Zhuoran; Abou-tok, Hosam; Meyer, Michael; Deineko, Viktor; Kassir, Sandy; Sidhu, Vishaldeep; Jessulat, Matthew; Scott, Nichollas E.; Xiong, Xuejian; Vlasblom, James; Prasad, Bhanu; Foster, Leonard J.; Alberio, Tiziana; Garavaglia, Barbara; Yu, Haiyuan; Bader, Gary D.; Nakamura, Ken; Parkinson, John; Babu, Mohan
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11383/2069047
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 30
  • ???jsp.display-item.citation.isi??? 29
social impact