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

Ramy H. Malty; Hiroyuki Aoki; Ashwani Kumar; Sadhna Phanse; Shahreen Amin; Qingzhou Zhang; Zoran Minic; Florian Goebels; Gabriel Musso; Zhuoran Wu; Hosam Abou-tok; Michael Meyer; Viktor Deineko; Sandy Kassir; Vishaldeep Sidhu; Matthew Jessulat; Nichollas E. Scott; Xuejian Xiong; James Vlasblom; Bhanu Prasad; Leonard J. Foster; Tiziana Alberio; Barbara Garavaglia; Haiyuan Yu; Gary D. Bader; Ken Nakamura; John Parkinson; Mohan Babu

doi:10.1016/j.cels.2017.10.010

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

Ramy H. Malty, Hiroyuki Aoki, Ashwani Kumar, Sadhna Phanse, Shahreen Amin, Qingzhou Zhang, Zoran Minic, Florian Goebels, Gabriel Musso, Zhuoran Wu, Hosam Abou-tok, Michael Meyer, Viktor Deineko, Sandy Kassir, Vishaldeep Sidhu, Matthew Jessulat, Nichollas E. Scott, Xuejian Xiong, James Vlasblom, Bhanu PrasadLeonard J. Foster, Tiziana Alberio, Barbara Garavaglia, Haiyuan Yu, Gary D. Bader, Ken Nakamura, John Parkinson, Mohan Babu

Fondazione IRCCS Istituto Neurologico "C. Besta"

Research output: Contribution to journal › Article › peer-review

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. Mitochondrial protein (MP) dysfunction has long been linked to neurodegenerative disorders (NDs), yet the molecular mechanisms underlying NDs have been obfuscated by the limited characterization of protein-protein interactions (PPIs) governing mitochondrial function. Through mass spectrometry analysis of affinity-purified mitochondrial fractions isolated from epitope-tagged human ND-linked MPs, Malty et al. report a high-confidence MP network with PPIs relevant for neurological function and reveal new mechanisms for MPs in redox homeostasis (SOD1-PRDX5) and NF-κB activation (IκBɛ- DLD or PINK1/PARKIN).

Original language	English
Pages (from-to)	564-577.e12
Journal	Cell Systems
Volume	5
Issue number	6
DOIs	https://doi.org/10.1016/j.cels.2017.10.010
Publication status	Published - Dec 27 2017

ASJC Scopus subject areas

Pathology and Forensic Medicine
Histology
Cell Biology

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10.1016/j.cels.2017.10.010

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Malty, R. H., Aoki, H., Kumar, A., Phanse, S., Amin, S., Zhang, Q., Minic, Z., Goebels, F., Musso, G., Wu, Z., Abou-tok, H., Meyer, M., Deineko, V., Kassir, S., Sidhu, V., Jessulat, M., Scott, N. E., Xiong, X., Vlasblom, J., ... Babu, M. (2017). A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling. Cell Systems, 5(6), 564-577.e12. https://doi.org/10.1016/j.cels.2017.10.010

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

In: Cell Systems, Vol. 5, No. 6, 27.12.2017, p. 564-577.e12.

Research output: Contribution to journal › Article › peer-review

Malty, RH, Aoki, H, Kumar, A, Phanse, S, Amin, S, Zhang, Q, Minic, Z, Goebels, F, Musso, G, Wu, Z, Abou-tok, H, Meyer, M, Deineko, V, Kassir, S, Sidhu, V, Jessulat, M, Scott, NE, Xiong, X, Vlasblom, J, Prasad, B, Foster, LJ, Alberio, T, Garavaglia, B, Yu, H, Bader, GD, Nakamura, K, Parkinson, J & Babu, M 2017, 'A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling', Cell Systems, vol. 5, no. 6, pp. 564-577.e12. https://doi.org/10.1016/j.cels.2017.10.010

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. / A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling. In: Cell Systems. 2017 ; Vol. 5, No. 6. pp. 564-577.e12.

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

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. Mitochondrial protein (MP) dysfunction has long been linked to neurodegenerative disorders (NDs), yet the molecular mechanisms underlying NDs have been obfuscated by the limited characterization of protein-protein interactions (PPIs) governing mitochondrial function. Through mass spectrometry analysis of affinity-purified mitochondrial fractions isolated from epitope-tagged human ND-linked MPs, Malty et al. report a high-confidence MP network with PPIs relevant for neurological function and reveal new mechanisms for MPs in redox homeostasis (SOD1-PRDX5) and NF-κB activation (IκBɛ- DLD or PINK1/PARKIN).",

author = "Malty, {Ramy H.} and Hiroyuki Aoki and Ashwani Kumar and Sadhna Phanse and Shahreen Amin and Qingzhou Zhang and Zoran Minic and Florian Goebels and Gabriel Musso and Zhuoran Wu and Hosam Abou-tok and Michael Meyer and Viktor Deineko and Sandy Kassir and Vishaldeep Sidhu and Matthew Jessulat and Scott, {Nichollas E.} and Xuejian Xiong and James Vlasblom and Bhanu Prasad and Foster, {Leonard J.} and Tiziana Alberio and Barbara Garavaglia and Haiyuan Yu and Bader, {Gary D.} and Ken Nakamura and John Parkinson and Mohan Babu",

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T1 - A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-κB Signaling

AU - Malty, Ramy H.

AU - Aoki, Hiroyuki

AU - Kumar, Ashwani

AU - Phanse, Sadhna

AU - Amin, Shahreen

AU - Zhang, Qingzhou

AU - Minic, Zoran

AU - Goebels, Florian

AU - Musso, Gabriel

AU - Wu, Zhuoran

AU - Abou-tok, Hosam

AU - Meyer, Michael

AU - Deineko, Viktor

AU - Kassir, Sandy

AU - Sidhu, Vishaldeep

AU - Jessulat, Matthew

AU - Scott, Nichollas E.

AU - Xiong, Xuejian

AU - Vlasblom, James

AU - Prasad, Bhanu

AU - Foster, Leonard J.

AU - Alberio, Tiziana

AU - Garavaglia, Barbara

AU - Yu, Haiyuan

AU - Bader, Gary D.

AU - Nakamura, Ken

AU - Parkinson, John

AU - Babu, Mohan

PY - 2017/12/27

Y1 - 2017/12/27

N2 - 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. Mitochondrial protein (MP) dysfunction has long been linked to neurodegenerative disorders (NDs), yet the molecular mechanisms underlying NDs have been obfuscated by the limited characterization of protein-protein interactions (PPIs) governing mitochondrial function. Through mass spectrometry analysis of affinity-purified mitochondrial fractions isolated from epitope-tagged human ND-linked MPs, Malty et al. report a high-confidence MP network with PPIs relevant for neurological function and reveal new mechanisms for MPs in redox homeostasis (SOD1-PRDX5) and NF-κB activation (IκBɛ- DLD or PINK1/PARKIN).

AB - 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. Mitochondrial protein (MP) dysfunction has long been linked to neurodegenerative disorders (NDs), yet the molecular mechanisms underlying NDs have been obfuscated by the limited characterization of protein-protein interactions (PPIs) governing mitochondrial function. Through mass spectrometry analysis of affinity-purified mitochondrial fractions isolated from epitope-tagged human ND-linked MPs, Malty et al. report a high-confidence MP network with PPIs relevant for neurological function and reveal new mechanisms for MPs in redox homeostasis (SOD1-PRDX5) and NF-κB activation (IκBɛ- DLD or PINK1/PARKIN).

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

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