Contents lists available at ScienceDirect BBA - Bioenergetics journal homepage: www.elsevier.com/locate/bbabio Review Expression and putative role of mitochondrial transport proteins in cancer ☆ Oleksandr Lytovchenko 1 , Edmund R.S. Kunji ⁎ Medical Research Council, Mitochondrial Biology Unit, Cambridge Biomedical Campus, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK ARTICLE INFO Keywords: Mitochondrial metabolism Regulation in cancer Transporters Mitochondrial carrier Pyruvate carrier Cancer metabolism ABSTRACT Cancer cells undergo major changes in energy and biosynthetic metabolism. One of them is the Warburg effect, in which pyruvate is used for fermentation rather for oxidative phosphorylation. Another major one is their increased reliance on glutamine, which helps to replenish the pool of Krebs cycle metabolites used for other purposes, such as amino acid or lipid biosynthesis. Mitochondria are central to these alterations, as the biochemical pathways linking these processes run through these organelles. Two membranes, an outer and inner membrane, surround mitochondria, the latter being impermeable to most organic compounds. Therefore, a large number of transport proteins are needed to link the biochemical pathways of the cytosol and mitochondrial matrix. Since the transport steps are relatively slow, it is expected that many of these transport steps are altered when cells become cancerous. In this review, changes in expression and regulation of these transport proteins are discussed as well as the role of the transported substrates. This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. 1. Alterations of mitochondrial metabolism It has been long established that metabolism of cancer cells is different from that of normal cells. In recent years, interest in this aspect of cancer has significantly increased and has lead to the provocative proposal that cancer is a metabolic disease, caused by metabolic defects [1,2]. Whether or not this is true, alterations of cellular metabolism represent a prominent hallmark of all cancers [3]. Most of these changes directly or indirectly involve mitochondria, thus making these organelles central players in defining the phenotypic characteristics of cancer cells. There is no consensus on the causal relationships between alterations occurring in mitochondria and carci- nogenesis, but parts of the puzzle are gradually starting to come together. In 1920s, Otto Warburg made an observation, which became one of the most famous, but at the same time highly misinterpreted and controversial observations in cancer biology. He found that cancer cells, unlike normal cells, maintain high levels of glycolysis even under conditions of sufficient oxygenation, or, in other words, they bypass the Pasteur effect. Warburg named this phenomenon “aerobic fermenta- tion”, but nowadays it is generally known as the “Warburg effect”– a term proposed by Efraim Racker in 1972 [4–6]. Warburg proposed the most straightforward and self-evident ex- planation: cancer cells need to rely glycolysis, because their respiratory chain does not function properly. Moreover, he stated that the defect in respiratory chain is the only primary cause of cancer, and all other manifestations are secondary to it. Nowadays we know that this “self- evident” explanation is wrong: cancer cells, in most cases, possess fully functional respiratory chains, which are responsible for the majority of ATP production [7,8]. Up-regulated glycolysis, however, serves other metabolic processes, providing building blocks for biosynthetic pro- cesses in the cell (Fig. 1). The Warburg effect is clearly the most famous metabolic phenotype in cancer, but definitely not the only one. Another important feature of most cancer cells is their increased reliance on glutamine, which is the most abundant amino acid in blood serum. Increased glutaminolysis helps to replenish the pool of Krebs cycle metabolites used for other purposes, such as amino acid or lipid biosynthesis [9–11]. In addition, mitochondria provide many crucial metabolites for iron sulfur cluster assembly, heme synthesis, sterol and lipid synthesis, and amino acid synthesis, degradation and interconver- sions – pathways, which can be highly relevant for cancer metabolism [12–17]. Moreover, mitochondria are key players in initiation and execution of apoptosis, and cancer cells need to deal with this aspect of mitochondrial function as well [18–20]. In this review we will discuss metabolite transport in processes altered in cancer, focusing on those aspects of metabolism that involve metabolite transport across the inner membrane of mitochondria and on the roles of the transported molecules in these processes. We do not http://dx.doi.org/10.1016/j.bbabio.2017.03.006 Received 14 December 2016; Received in revised form 20 February 2017; Accepted 21 March 2017 ☆ This article is part of a Special Issue entitled Mitochondria in Cancer, edited by Giuseppe Gasparre, Rodrigue Rossignol and Pierre Sonveaux. ⁎ Corresponding author. 1 Current address; Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Retzius väg 8, Stockholm, Sweden. E-mail addresses: ek@mrc-mbu.cam.ac.uk, edmund.kunji@mrc-mbu.cam.ac.uk (E.R.S. Kunji). BBA - Bioenergetics xxx (xxxx) xxx–xxx 0005-2728/ © 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/). Please cite this article as: Lytovchenko, O., BBA - Bioenergetics (2017), http://dx.doi.org/10.1016/j.bbabio.2017.03.006