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Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role

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Abstract

Mitochondria are recognized as the main source of ATP to meet the energy demands of the cell. ATP production occurs by oxidative phosphorylation when electrons are transported through the electron transport chain (ETC) complexes and develop the proton motive force across the inner mitochondrial membrane that is used for ATP synthesis. Studies since the 1960s have been concentrated on the two models of structural organization of ETC complexes known as “solid-state” and “fluid-state” models. However, advanced new techniques such as blue-native gel electrophoresis, mass spectroscopy, and cryogenic electron microscopy for analysis of macromolecular protein complexes provided new data in favor of the solid-state model. According to this model, individual ETC complexes are assembled into macromolecular structures known as respiratory supercomplexes (SCs). A large number of studies over the last 20 years proposed the potential role of SCs to facilitate substrate channeling, maintain the integrity of individual ETC complexes, reduce electron leakage and production of reactive oxygen species, and prevent excessive and random aggregation of proteins in the inner mitochondrial membrane. However, many other studies have challenged the proposed functional role of SCs. Recently, a third model known as the “plasticity” model was proposed that partly reconciles both “solid-state” and “fluid-state” models. According to the “plasticity” model, respiratory SCs can co-exist with the individual ETC complexes. To date, the physiological role of SCs remains unknown, although several studies using tissue samples of patients or animal/cell models of human diseases revealed an associative link between functional changes and the disintegration of SC assembly. This review summarizes and discusses previous studies on the mechanisms and regulation of SC assembly under physiological and pathological conditions.

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Abbreviations

ANT:

adenine nucleotide translocase

BN-PAGE:

blue native polyacrylamide gel electrophoresis

CI:

complex I

CII:

complex II

CIII:

complex III

CIV:

complex IV

CV:

complex V

cryo-EM:

cryogenic electron microscopy

ETC:

electron transport chain

IMM:

inner mitochondrial membrane

IR:

ischemia-reperfusion

mtROS:

mitochondrial ROS

OPA1:

optic atrophy 1 protein

OXPHOS:

oxidative phosphorylation

PTP:

permeability transition pore

ROS:

reactive oxygen species

SC:

supercomplex

SCAF1:

supercomplex assembly factor 1

SLP2:

stomatin-like protein 2

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Acknowledgments

The authors apologize to all colleagues whose important studies were not cited due to space restriction.

Funding

This study was supported by the National Institute of General Medical Sciences (Grant SC1GM128210 to Sa.J.) and the National Heart, Lung, and Blood Institute (Grant R01 HL-131673 to A.K.S.C.) of the National Institutes of Health, National Science Foundation (Grant 2006477 to Sa.J), and Advancing A Healthier Wisconsin (AHW; Grant 5520444 to A.K.S.C.).

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Authors and Affiliations

  1. Department of Physiology, University of Puerto Rico School of Medicine, San Juan, PR, 00936-5067, USA

    Sabzali Javadov, Sehwan Jang & Xavier R. Chapa-Dubocq

  2. Department of Biochemistry, Sechenov First Moscow State Medical University, 119991, Moscow, Russia

    Zaza Khuchua

  3. Division of Molecular and Cardiovascular Biology, Cincinnati Children’s Medical Center, Cincinnati, OH, 45229, USA

    Zaza Khuchua

  4. Department of Anesthesiology and Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Amadou KS Camara

  5. Cancer Center, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Amadou KS Camara

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  1. Sabzali Javadov
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  2. Sehwan Jang
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  3. Xavier R. Chapa-Dubocq
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  4. Zaza Khuchua
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  5. Amadou KS Camara
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Sa.J. generated conceptual outline and wrote the first draft of the manuscript. Se.J. designed figures. All authors jointly performed the literature search and completed final manuscript. All authors read and approved the final manuscript.

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Correspondence to Sabzali Javadov.

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Javadov, S., Jang, S., Chapa-Dubocq, X.R. et al. Mitochondrial respiratory supercomplexes in mammalian cells: structural versus functional role. J Mol Med 99, 57–73 (2021). https://doi.org/10.1007/s00109-020-02004-8

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