Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov; Shannon Coy; Boryana Petrova; Margaret Dreishpoon; Ana Verma; Mai Abdusamad; Jordan Rossen; Lena Joesch-Cohen; Ranad Humeidi; Ryan D. Spangler; John K. Eaton; Evgeni Frenkel; Mustafa Kocak; Steven M. Corsello; Svetlana Lutsenko; Naama Kanarek; Sandro Santagata; Todd R. Golub

doi:10.1126/science.abf0529

Copper induces cell death by targeting lipoylated TCA cycle proteins

Peter Tsvetkov, Shannon Coy, Boryana Petrova, Margaret Dreishpoon, Ana Verma, Mai Abdusamad, Jordan Rossen, Lena Joesch-Cohen, Ranad Humeidi, Ryan D. Spangler, John K. Eaton, Evgeni Frenkel, Mustafa Kocak, Steven M. Corsello, Svetlana Lutsenko, Naama Kanarek, Sandro Santagata, Todd R. Golub

School of Medicine

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

Abstract

Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

Original language	English (US)
Pages (from-to)	1254-1261
Number of pages	8
Journal	Science
Volume	375
Issue number	6586
DOIs	https://doi.org/10.1126/science.abf0529
State	Published - Mar 18 2022

ASJC Scopus subject areas

General

Access to Document

10.1126/science.abf0529

Cite this

Tsvetkov, P., Coy, S., Petrova, B., Dreishpoon, M., Verma, A., Abdusamad, M., Rossen, J., Joesch-Cohen, L., Humeidi, R., Spangler, R. D., Eaton, J. K., Frenkel, E., Kocak, M., Corsello, S. M., Lutsenko, S., Kanarek, N., Santagata, S., & Golub, T. R. (2022). Copper induces cell death by targeting lipoylated TCA cycle proteins. Science, 375(6586), 1254-1261. https://doi.org/10.1126/science.abf0529

Tsvetkov, P, Coy, S, Petrova, B, Dreishpoon, M, Verma, A, Abdusamad, M, Rossen, J, Joesch-Cohen, L, Humeidi, R, Spangler, RD, Eaton, JK, Frenkel, E, Kocak, M, Corsello, SM, Lutsenko, S, Kanarek, N, Santagata, S & Golub, TR 2022, 'Copper induces cell death by targeting lipoylated TCA cycle proteins', Science, vol. 375, no. 6586, pp. 1254-1261. https://doi.org/10.1126/science.abf0529

@article{2c42ec89764749d9b3c4b29159a90a28,

title = "Copper induces cell death by targeting lipoylated TCA cycle proteins",

abstract = "Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.",

author = "Peter Tsvetkov and Shannon Coy and Boryana Petrova and Margaret Dreishpoon and Ana Verma and Mai Abdusamad and Jordan Rossen and Lena Joesch-Cohen and Ranad Humeidi and Spangler, {Ryan D.} and Eaton, {John K.} and Evgeni Frenkel and Mustafa Kocak and Corsello, {Steven M.} and Svetlana Lutsenko and Naama Kanarek and Sandro Santagata and Golub, {Todd R.}",

year = "2022",

month = mar,

day = "18",

doi = "10.1126/science.abf0529",

language = "English (US)",

volume = "375",

pages = "1254--1261",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6586",

}

TY - JOUR

T1 - Copper induces cell death by targeting lipoylated TCA cycle proteins

AU - Tsvetkov, Peter

AU - Coy, Shannon

AU - Petrova, Boryana

AU - Dreishpoon, Margaret

AU - Verma, Ana

AU - Abdusamad, Mai

AU - Rossen, Jordan

AU - Joesch-Cohen, Lena

AU - Humeidi, Ranad

AU - Spangler, Ryan D.

AU - Eaton, John K.

AU - Frenkel, Evgeni

AU - Kocak, Mustafa

AU - Corsello, Steven M.

AU - Lutsenko, Svetlana

AU - Kanarek, Naama

AU - Santagata, Sandro

AU - Golub, Todd R.

PY - 2022/3/18

Y1 - 2022/3/18

N2 - Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

AB - Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85126660545&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85126660545&partnerID=8YFLogxK

U2 - 10.1126/science.abf0529

DO - 10.1126/science.abf0529

M3 - Article

C2 - 35298263

AN - SCOPUS:85126660545

SN - 0036-8075

VL - 375

SP - 1254

EP - 1261

JO - Science

JF - Science

IS - 6586

ER -

Copper induces cell death by targeting lipoylated TCA cycle proteins

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this