CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells

Cho Cho Aye; Dean E. Hammond; Sergio Rodriguez-Cuenca; Mary K. Doherty; Phillip D. Whitfield; Marie M. Phelan; Chenjing Yang; Rafael Perez-Perez; Xiaoxin Li; Angels Diaz-Ramos; Gopal Peddinti; Matej Orešič; Antonio Vidal-Puig; Antonio Zorzano; Cristina Ugalde; Silvia Mora

doi:10.3390/ijms24043399

CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells

Cho Cho Aye
, Dean E. Hammond
, Sergio Rodriguez-Cuenca
, Mary K. Doherty
, Phillip D. Whitfield
, Marie M. Phelan
, Chenjing Yang
, Rafael Perez-Perez
, Xiaoxin Li
, Angels Diaz-Ramos
, Gopal Peddinti
, Matej Orešič
, Antonio Vidal-Puig
, Antonio Zorzano
, Cristina Ugalde
, Silvia Mora^*

^*Corresponding author for this work

Bioanalytics and biological data science

University of Liverpool
University of Cambridge
University of the Highlands and Islands
Universidad Complutense de Madrid
Institute for Research in Biomedicine (IRB Barcelona)
Örebro University

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

5 Citations (Scopus)

Abstract

CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

Original language	English
Article number	3399
Number of pages	17
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	4
DOIs	https://doi.org/10.3390/ijms24043399
Publication status	Published - Feb 2023
MoE publication type	A1 Journal article-refereed

Funding

This work was supported by the University of Liverpool, a research grant from the European Commission (Framework 7 grant HEALTH-F4-2008-223450 to S.M., A.Z., A.V.-P., M.O.), by National Institute of Health RO1 grant GM105781 (to C.U.) and by Instituto de Salud Carlos III-MINECO/European FEDER Funds grant PI17-00048 (to C.U.). M.K.D. and P.D.W. acknowledge funding from European Regional Development Fund, Scottish Funding Council and Highlands and Islands Enterprise.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

CBL
glucose transport
insulin resistance
insulin signalling
mitochondria
SORBS1
Mitochondria, Muscle/metabolism
Muscle Cells/metabolism
Mitochondria/metabolism
Insulin Resistance
Animals
Proto-Oncogene Proteins c-cbl/metabolism
Energy Metabolism
Cell Respiration
Insulin/metabolism
Mice

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10.3390/ijms24043399Licence: CC BY

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Aye, C. C., Hammond, D. E., Rodriguez-Cuenca, S., Doherty, M. K., Whitfield, P. D., Phelan, M. M., Yang, C., Perez-Perez, R., Li, X., Diaz-Ramos, A., Peddinti, G., Orešič, M., Vidal-Puig, A., Zorzano, A., Ugalde, C., & Mora, S. (2023). CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells. International Journal of Molecular Sciences, 24(4), Article 3399. https://doi.org/10.3390/ijms24043399

@article{1df053a1786d41769e7112990f77bc54,

title = "CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells",

abstract = "CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.",

keywords = "CBL, glucose transport, insulin resistance, insulin signalling, mitochondria, SORBS1, Mitochondria, Muscle/metabolism, Muscle Cells/metabolism, Mitochondria/metabolism, Insulin Resistance, Animals, Proto-Oncogene Proteins c-cbl/metabolism, Energy Metabolism, Cell Respiration, Insulin/metabolism, Mice",

author = "Aye, \{Cho Cho\} and Hammond, \{Dean E.\} and Sergio Rodriguez-Cuenca and Doherty, \{Mary K.\} and Whitfield, \{Phillip D.\} and Phelan, \{Marie M.\} and Chenjing Yang and Rafael Perez-Perez and Xiaoxin Li and Angels Diaz-Ramos and Gopal Peddinti and Matej Ore{\v s}i{\v c} and Antonio Vidal-Puig and Antonio Zorzano and Cristina Ugalde and Silvia Mora",

note = "Funding Information: This work was supported by the University of Liverpool, a research grant from the European Commission (Framework 7 grant HEALTH-F4-2008-223450 to S.M., A.Z., A.V.-P., M.O.), by National Institute of Health RO1 grant GM105781 (to C.U.) and by Instituto de Salud Carlos III-MINECO/European FEDER Funds grant PI17-00048 (to C.U.). M.K.D. and P.D.W. acknowledge funding from European Regional Development Fund, Scottish Funding Council and Highlands and Islands Enterprise. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = feb,

doi = "10.3390/ijms24043399",

language = "English",

volume = "24",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "MDPI",

number = "4",

}

Aye, CC, Hammond, DE, Rodriguez-Cuenca, S, Doherty, MK, Whitfield, PD, Phelan, MM, Yang, C, Perez-Perez, R, Li, X, Diaz-Ramos, A, Peddinti, G, Orešič, M, Vidal-Puig, A, Zorzano, A, Ugalde, C & Mora, S 2023, 'CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells', International Journal of Molecular Sciences, vol. 24, no. 4, 3399. https://doi.org/10.3390/ijms24043399

TY - JOUR

T1 - CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells

AU - Aye, Cho Cho

AU - Hammond, Dean E.

AU - Rodriguez-Cuenca, Sergio

AU - Doherty, Mary K.

AU - Whitfield, Phillip D.

AU - Phelan, Marie M.

AU - Yang, Chenjing

AU - Perez-Perez, Rafael

AU - Li, Xiaoxin

AU - Diaz-Ramos, Angels

AU - Peddinti, Gopal

AU - Orešič, Matej

AU - Vidal-Puig, Antonio

AU - Zorzano, Antonio

AU - Ugalde, Cristina

AU - Mora, Silvia

N1 - Funding Information: This work was supported by the University of Liverpool, a research grant from the European Commission (Framework 7 grant HEALTH-F4-2008-223450 to S.M., A.Z., A.V.-P., M.O.), by National Institute of Health RO1 grant GM105781 (to C.U.) and by Instituto de Salud Carlos III-MINECO/European FEDER Funds grant PI17-00048 (to C.U.). M.K.D. and P.D.W. acknowledge funding from European Regional Development Fund, Scottish Funding Council and Highlands and Islands Enterprise. Publisher Copyright: © 2023 by the authors.

PY - 2023/2

Y1 - 2023/2

N2 - CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

AB - CBL is rapidly phosphorylated upon insulin receptor activation. Mice whole body CBL depletion improved insulin sensitivity and glucose clearance; however, the precise mechanisms remain unknown. We depleted either CBL or its associated protein SORBS1/CAP independently in myocytes and assessed mitochondrial function and metabolism compared to control cells. CBL- and CAP-depleted cells showed increased mitochondrial mass with greater proton leak. Mitochondrial respiratory complex I activity and assembly into respirasomes were reduced. Proteome profiling revealed alterations in proteins involved in glycolysis and fatty acid degradation. Our findings demonstrate CBL/CAP pathway couples insulin signaling to efficient mitochondrial respiratory function and metabolism in muscle.

KW - CBL

KW - glucose transport

KW - insulin resistance

KW - insulin signalling

KW - mitochondria

KW - SORBS1

KW - Mitochondria, Muscle/metabolism

KW - Muscle Cells/metabolism

KW - Mitochondria/metabolism

KW - Insulin Resistance

KW - Animals

KW - Proto-Oncogene Proteins c-cbl/metabolism

KW - Energy Metabolism

KW - Cell Respiration

KW - Insulin/metabolism

KW - Mice

UR - https://www.scopus.com/pages/publications/85149028808

U2 - 10.3390/ijms24043399

DO - 10.3390/ijms24043399

M3 - Article

C2 - 36834818

AN - SCOPUS:85149028808

SN - 1661-6596

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 4

M1 - 3399

ER -

CBL/CAP Is Essential for Mitochondria Respiration Complex I Assembly and Bioenergetics Efficiency in Muscle Cells

Abstract

Funding

UN SDGs

Keywords

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