The 2-oxoglutarate/malate Carrier Extends the Family of Mitochondrial Carriers Capable of Fatty Acid and 2,4-dinitrophenol-activated Proton Transport

Overview

Journal Acta Physiol (Oxf)

Specialty Physiology

Date 2024 Apr 5

PMID 38577966

Authors

Kristina Zuna

Tatyana Tyschuk

Taraneh Beikbaghban

Felix Sternberg

Jurgen Kreiter

Elena E Pohl

Affiliations

Soon will be listed here.

Abstract

Aims: Metabolic reprogramming in cancer cells has been linked to mitochondrial dysfunction. The mitochondrial 2-oxoglutarate/malate carrier (OGC) has been suggested as a potential target for preventing cancer progression. Although OGC is involved in the malate/aspartate shuttle, its exact role in cancer metabolism remains unclear. We aimed to investigate whether OGC may contribute to the alteration of mitochondrial inner membrane potential by transporting protons.

Methods: The expression of OGC in mouse tissues and cancer cells was investigated by PCR and Western blot analysis. The proton transport function of recombinant murine OGC was evaluated by measuring the membrane conductance (G) of planar lipid bilayers. OGC-mediated substrate transport was measured in proteoliposomes using C-malate.

Results: OGC increases proton G only in the presence of natural (long-chain fatty acids, FA) or chemical (2,4-dinitrophenol) protonophores. The increase in OGC activity directly correlates with the increase in the number of unsaturated bonds of the FA. OGC substrates and inhibitors compete with FA for the same protein binding site. Arginine 90 was identified as a critical amino acid for the binding of FA, ATP, 2-oxoglutarate, and malate, which is a first step towards understanding the OGC-mediated proton transport mechanism.

Conclusion: OGC extends the family of mitochondrial transporters with dual function: (i) metabolite transport and (ii) proton transport facilitated in the presence of protonophores. Elucidating the contribution of OGC to uncoupling may be essential for the design of targeted drugs for the treatment of cancer and other metabolic diseases.

Citing Articles

Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond.

Pohl E, Vazdar M, Kreiter J Protein Sci. 2025; 34(3):e70047.

PMID: 39969060 PMC: 11837047. DOI: 10.1002/pro.70047.

The 2-oxoglutarate/malate carrier extends the family of mitochondrial carriers capable of fatty acid and 2,4-dinitrophenol-activated proton transport.

Zuna K, Tyschuk T, Beikbaghban T, Sternberg F, Kreiter J, Pohl E Acta Physiol (Oxf). 2024; 240(6):e14143.

PMID: 38577966 PMC: 11475482. DOI: 10.1111/apha.14143.

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