SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes

Naif A.M. Almontashiri; Hsiao-Huei Chen; Ryan J. Mailloux; Takashi Tatsuta; Allen C.T. Teng; Ahmad B. Mahmoud; Tiffany Ho; Nicolas Stewart; Peter Rippstein; Mary Ellen Harper; Robert Roberts; Christina Willenborg; Jeanette Erdmann; Annalisa Pastore; Heidi M. McBride; Thomas Langer; Alexandre F.R. Stewart

doi:10.1016/j.celrep.2014.03.051

SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes

Naif A.M. Almontashiri, Hsiao-Huei Chen, Ryan J. Mailloux, Takashi Tatsuta, Allen C.T. Teng, Ahmad B. Mahmoud, Tiffany Ho, Nicolas Stewart, Peter Rippstein, Mary Ellen Harper, Robert Roberts, Christina Willenborg, Jeanette Erdmann, Annalisa Pastore, Heidi M. McBride, Thomas Langer, Alexandre F.R. Stewart

University of Brighton

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

Abstract

Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

Original language	English
Journal	Cell Reports
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.03.051
Publication status	Published - 8 May 2014

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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Nicolas Stewart
- N.Stewartbrighton.acuk
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Almontashiri, N. A. M., Chen, H-H., Mailloux, R. J., Tatsuta, T., Teng, A. C. T., Mahmoud, A. B., Ho, T., Stewart, N., Rippstein, P., Harper, M. E., Roberts, R., Willenborg, C., Erdmann, J., Pastore, A., McBride, H. M., Langer, T., & Stewart, A. F. R. (2014). SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes. Cell Reports, 7(3). https://doi.org/10.1016/j.celrep.2014.03.051

@article{b7fa196047ec446799670b8ae1784713,

title = "SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes",

abstract = "Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.",

author = "Almontashiri, {Naif A.M.} and Hsiao-Huei Chen and Mailloux, {Ryan J.} and Takashi Tatsuta and Teng, {Allen C.T.} and Mahmoud, {Ahmad B.} and Tiffany Ho and Nicolas Stewart and Peter Rippstein and Harper, {Mary Ellen} and Robert Roberts and Christina Willenborg and Jeanette Erdmann and Annalisa Pastore and McBride, {Heidi M.} and Thomas Langer and Stewart, {Alexandre F.R.}",

note = "This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).",

year = "2014",

month = may,

day = "8",

doi = "10.1016/j.celrep.2014.03.051",

language = "English",

volume = "7",

journal = "Cell Reports",

issn = "2211-1247",

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Almontashiri, NAM, Chen, H-H, Mailloux, RJ, Tatsuta, T, Teng, ACT, Mahmoud, AB, Ho, T, Stewart, N, Rippstein, P, Harper, ME, Roberts, R, Willenborg, C, Erdmann, J, Pastore, A, McBride, HM, Langer, T & Stewart, AFR 2014, 'SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes', Cell Reports, vol. 7, no. 3. https://doi.org/10.1016/j.celrep.2014.03.051

TY - JOUR

T1 - SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes

AU - Almontashiri, Naif A.M.

AU - Chen, Hsiao-Huei

AU - Mailloux, Ryan J.

AU - Tatsuta, Takashi

AU - Teng, Allen C.T.

AU - Mahmoud, Ahmad B.

AU - Ho, Tiffany

AU - Stewart, Nicolas

AU - Rippstein, Peter

AU - Harper, Mary Ellen

AU - Roberts, Robert

AU - Willenborg, Christina

AU - Erdmann, Jeanette

AU - Pastore, Annalisa

AU - McBride, Heidi M.

AU - Langer, Thomas

AU - Stewart, Alexandre F.R.

N1 - This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

PY - 2014/5/8

Y1 - 2014/5/8

N2 - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

AB - Mitochondrial production of reactive oxygen species (ROS) affects many processes in health and disease. SPG7 assembles with AFG3L2 into the mAAA protease at the inner membrane of mitochondria, degrades damaged proteins, and regulates the synthesis of mitochondrial ribosomes. SPG7 is cleaved and activated by AFG3L2 upon assembly. A variant in SPG7 that replaces arginine 688 with glutamine (Q688) is associated with several phenotypes, including toxicity of chemotherapeutic agents, type 2 diabetes mellitus, and (as reported here) coronary artery disease. We demonstrate that SPG7 processing is regulated by tyrosine phosphorylation of AFG3L2. Carriers of Q688 bypass this regulation and constitutively process and activate SPG7 mAAA protease. Cells expressing Q688 produce higher ATP levels and ROS, promoting cell proliferation. Our results thus reveal an unexpected link between the phosphorylation-dependent regulation of the mitochondria mAAA protease affecting ROS production and several clinical phenotypes.

U2 - 10.1016/j.celrep.2014.03.051

DO - 10.1016/j.celrep.2014.03.051

M3 - Article

SN - 2211-1247

VL - 7

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

SPG7 variant escapes phosphorylation-regulated processing by AFG3L2, elevates mitochondrial ROS, and is associated with multiple clinical phenotypes

Abstract

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Nicolas Stewart

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