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Review

Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier

1
Brazilian Biosciences National Laboratory, Center for Research in Energy and Materials, Campinas 13083-970, Brazil
2
Postgraduate program in Biosciences and Technology of Bioactive Products, Institute of Biology, University of Campinas, Campinas 13083-970, Brazil
3
School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK
4
São Carlos Institute of Physics, University of São Paulo, São Carlos 13563-120, Brazil
5
Membrane Protein Laboratory, Diamond Light Source Limited, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK
*
Author to whom correspondence should be addressed.
Current address: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Australia.
Current address: McArdle Laboratory for Cancer Research, Department of Oncology, School of Medicine and Public Health, University of Wisconsin at Madison, Madison, WI 53705, USA.
§
Current address: National Physical Laboratory, Teddington, Middlesex TW11 0LW, UK.
Biology 2020, 9(11), 407; https://doi.org/10.3390/biology9110407
Received: 16 October 2020 / Revised: 14 November 2020 / Accepted: 17 November 2020 / Published: 19 November 2020
The atomic structure of a biological macromolecule determines its function. Discovering how one or more amino acid chains fold and interact to form a protein complex is critical, from understanding the most fundamental cellular processes to developing new therapies. However, this is far from a straightforward task, especially when studying a membrane protein. The functional link between the oligomeric state and complex composition of the proteins involved in the active mitochondrial transport of cytosolic pyruvate is a decades-old question but remains urgent. We present a brief historical review beginning with the identification of the so-called mitochondrial pyruvate carrier (MPC) proteins, followed by a rigorous conceptual analysis of technical approaches in more recent biochemical studies that seek to isolate and reconstitute the functional MPC complex(es) in vitro. We correlate these studies with early kinetic observations and current experimental and computational knowledge to assess their main contributions, identify gaps, resolve ambiguities, and better define the research goal.
The molecular identity of the mitochondrial pyruvate carrier (MPC) was presented in 2012, forty years after the active transport of cytosolic pyruvate into the mitochondrial matrix was first demonstrated. An impressive amount of in vivo and in vitro studies has since revealed an unexpected interplay between one, two, or even three protein subunits defining different functional MPC assemblies in a metabolic-specific context. These have clear implications in cell homeostasis and disease, and on the development of future therapies. Despite intensive efforts by different research groups using state-of-the-art computational tools and experimental techniques, MPCs’ structure-based mechanism remains elusive. Here, we review the current state of knowledge concerning MPCs’ molecular structures by examining both earlier and recent studies and presenting novel data to identify the regulatory, structural, and core transport activities to each of the known MPC subunits. We also discuss the potential application of cryogenic electron microscopy (cryo-EM) studies of MPC reconstituted into nanodiscs of synthetic copolymers for solving human MPC2. View Full-Text
Keywords: mitochondrial pyruvate carrier; membrane proteins; structure; function mitochondrial pyruvate carrier; membrane proteins; structure; function
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MDPI and ACS Style

Quesñay, J.E.N.; Pollock, N.L.; Nagampalli, R.S.K.; Lee, S.C.; Balakrishnan, V.; Dias, S.M.G.; Moraes, I.; Dafforn, T.R.; Ambrosio, A.L.B. Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier. Biology 2020, 9, 407. https://doi.org/10.3390/biology9110407

AMA Style

Quesñay JEN, Pollock NL, Nagampalli RSK, Lee SC, Balakrishnan V, Dias SMG, Moraes I, Dafforn TR, Ambrosio ALB. Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier. Biology. 2020; 9(11):407. https://doi.org/10.3390/biology9110407

Chicago/Turabian Style

Quesñay, José E.N., Naomi L. Pollock, Raghavendra S.K. Nagampalli, Sarah C. Lee, Vijayakumar Balakrishnan, Sandra M.G. Dias, Isabel Moraes, Tim R. Dafforn, and Andre L.B. Ambrosio 2020. "Insights on the Quest for the Structure–Function Relationship of the Mitochondrial Pyruvate Carrier" Biology 9, no. 11: 407. https://doi.org/10.3390/biology9110407

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