MITOCH-01005; No of Pages 6 Mitochondrion xxx (2015) xxx–xxx

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Mitochondrion journal homepage: www.elsevier.com/locate/mito

Review

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The mitochondrial unselective channel in Saccharomyces cerevisiae

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Manuel Gutiérrez-Aguilar a,⁎, Salvador Uribe-Carvajal b

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Article history: Received 1 February 2015 Received in revised form 3 April 2015 Accepted 8 April 2015 Available online xxxx

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Keywords: Yeast mitochondria Permeability transition pore Mitochondrial unselective channel Mitochondrial evolution Bioenergetics Cell death

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1. Introduction . . . . . . . . . . . . . . . . . . . . 2. Regulatory features of the ScMUC . . . . . . . . . . 3. Relations between structure and function of the ScMUC 4. The Ca2 +-induced permeability transition in S. cerevisiae 5. The role of mitochondrial cyclophilin . . . . . . . . 6. Physiological roles of the ScMUC . . . . . . . . . . . 7. Concluding remarks . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

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The endosymbiont model proposes that mitochondria originated from an α-proteobacteria that learned to live inside an eukaryotic ancestor (Gray et al., 1999). These endosymbionts became mitochondria once protein and metabolite carrier proteins were inserted

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Opening of the mitochondrial permeability transition (MPT) pore mediates the increase in the unselective permeability to ions and small molecules across the inner mitochondrial membrane. MPT results from the opening of channels of unknown identity in mitochondria from plants, animals and yeast. However, the effectors and conditions required for MPT to occur in different species are remarkably disparate. Here we critically review previous and recent findings concerning the mitochondrial unselective channel of the yeast Saccharomyces cerevisiae to determine if it can be considered a counterpart of the mammalian MPT pore. © 2015 Elsevier B.V. and Mitochondria Research Society.

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Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA Molecular Genetics Department, Instituto de Fisiología Celular, UNAM, Mexico City, Mexico

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Abbreviations: MPT, mitochondrial permeability transition; ScMUC, Saccharomyces cerevisiae mitochondrial unselective channel; ROS, reactive oxygen species; CsA, cyclosporine A; CypD, cyclophilin D; ANT, adenine-nucleotide translocase; VDAC, voltage-dependent anion channel; PiC, phosphate carrier; TEA, triethanolamine; dVO4, decavanadate; dUb, decylubiquinone. ⁎ Corresponding author at: Dalton Cardiovascular Research Center, University of Missouri-Columbia, 134 Research Park Dr. Columbia, MO 65211, USA. Tel.: +1 573 882 5052. E-mail address: [email protected] (M. Gutiérrez-Aguilar).

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in their outer and inner membranes so the host cell could manage mitochondrial protein content and exchange ions and molecules thus controlling aerobic metabolism (Cavalier-Smith, 2006). In mitochondria, oxidative phosphorylation can behave as a double edge sword since the highly efficient oxidative metabolism can produce toxic reactive oxygen species (ROS) at a high rate (Korshunov et al., 1997). ROS and calcium ions can alter molecules in the mitochondrial inner membrane thus affecting the permeability status of the mitochondrion (Lindsay et al., 2015). This permeability shift, also known as the mitochondrial permeability transition (MPT) can lead to organelle swelling, ATP depletion and cell death (for a recent perspective see Kwong and Molkentin, 2015). In mammalian mitochondria, a pore allowing unselective traffic of solutes with a molecular exclusion cutoff around 1.5 kDa was reported (Haworth and Hunter, 1979) and termed the mitochondrial permeability transition (MPT) pore (for a review see Bernardi, 2013). In

http://dx.doi.org/10.1016/j.mito.2015.04.002 1567-7249/© 2015 Elsevier B.V. and Mitochondria Research Society.

Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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3. Relations between structure and function of the ScMUC

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In 1997, Jung and collaborators showed that ScMUC and the MPT pore have comparable dimensions. Comparison between both pores relied on solute size exclusion experiments using polyethylene glycols of increasing molecular weight under isosmotic conditions. Such

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4. The Ca2+-induced permeability transition in S. cerevisiae

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The ScMUC has been considered unrelated to the mammalian MPT (Halestrap, 2010). The reasons underlying such view are tangible: This transition is inhibited by Pi whereas Ca2 + only activates MPT in the presence of selective ionophores (Carraro et al., 2014). A closer look at these differences may be explained in evolutionary terms. S. cerevisiae mitochondria lack a mitochondrial Ca2+ uniporter (MCU) (Uribe et al., 1992). This characteristic helped to determine the identity of the core component of the uniporter complex by ruling out MCU protein

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During the 90's, different groups studied channel-dependent mitochondrial unselective transport of molecules triggered by phosphate depletion, high respiratory rates and ATP/GDP addition in the baker's yeast (Guérin et al., 1994; Prieto et al., 1995). Although straindependent differences were found on the transported molecules, the consensus was that these permeabilities were unselective. More recently, Bradshaw and Pfeiffer (2013) have shown that the ATP synthase inhibitor oligomycin abolishes strain-dependent differences on ScMUC activity. While the reasons underlying such result remain to be understood, the authors proposed that oligomycin could bind ATP synthase to induce opening of the ScMUC mediated by high matrix space pH. Indeed, pioneering work by Velours et al. (1977) showed that low pH potently inhibited ultrastructural changes in isolated mitochondria that were associated with ScMUC closure by Jung et al. (1997). The ScMUC and MPT pore are modulated through respiratory chain activity. While rotenone — an inhibitor of respiratory complex I — inhibits the MTP pore (Li et al., 2012), the ATP-driven ScMUC can be suppressed with flavone by targeting the external NADH-dehydrogenase (Manon, 1999). In the case of the MPT pore, rotenone has been determined to be as potent as CsA to inhibit pore opening in tissues where CypD is less expressed. Conversely, the mechanism by which flavone inhibits the ScMUC appears to be more related to the respiratory chain per se as titration with KCN can decrease pore activity (Manon, 1999). Thus, if the pore's core involves similar proteins in yeast and mammalian mitochondria, then respiratory Complex I could only be considered a MPT regulatory component, as this multi-subunit complex is remarkably absent in S. cerevisiae (Gutiérrez-Aguilar et al., 2014b). Indeed, Giorgio and colleagues have nicely demonstrated that Complex I does not form channels when reconstituted in lipid bilayers (Giorgio et al., 2013).

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experiments revealed that the ScMUC allowed trafficking of solutes with a MW lower than 1.5 kDa. Antithetically, the authors also showed that the swelling extent upon ScMUC and MPT pore opening differed in magnitude potentially due to ultrastructural differences between yeast and mammalian mitochondria. This means that yeast mitochondria have relatively few cristae, thus limiting the ScMUC-mediated increase in matrix volume and the resultant swelling profile measured with traditional methods. One of the most known hallmarks of the MPT pore has been its modulation with selective ligands of the mitochondrial solute carrier family. In particular, it's modulation with bongkrekic acid, ADP and atractyloside. This has led several groups to propose that its protein target, the adenine nucleotide translocator (ANT) is the pore's core component (Halestrap et al., 1997). However, this hypothesis has been challenged through biochemical (Novgorodov et al., 1994) and genetic approaches i.e. in yeast and mice lacking ANT isoforms, MPT is still detected (Kokoszka et al., 2004; Roucou et al., 1997). This has led researchers to either modify their proposal, suggesting that the mitochondrial phosphate carrier is the actual pore-forming protein (Leung et al., 2008) or to propose that ANT ligands exert their inhibitory or stimulating function on MPT pore through inner-membrane surface potential modification (Di Lisa et al., 2011). The latter hypothesis seems more likely as yeast mitochondria completely lacking PiC and mammalian mitochondria where PiC levels were decreased through siRNA mediated protein knockdown, or tissue-specific PiC deletion still undergoes MPT (Gutiérrez-Aguilar et al., 2010, 2014a; Kwong et al., 2014; Varanyuwatana and Halestrap, 2011). Nonetheless, it is worth to mention that the pore detected in yeast presents differences when compared to its wild type counterpart. For instance, isolated yeast mitochondria from a PiC-deficient strain are resistant to mersalyl-induced, Pi-inhibited ScMUC opening (Gutiérrez-Aguilar et al., 2010). Although we have proposed that PiC is a complement of the ScMUC, Bradshaw and Pfeiffer (2013) have proposed that phosphate inhibits ScMUC by binding a site on the matrix space side of the inner membrane in addition to its known effect on matrix pH (Bradshaw and Pfeiffer, 2013). Based on the article by Giorgio et al. (2013) entitled “Dimers of mitochondrial ATP synthase form the permeability transition pore”, Bernardi and Di Lisa (2015) have proposed that such binding site could be ATP synthase. As an epilogue for the “mitochondrial carrier hypothesis”, it is now possible to conclude that mitochondrial solute carriers are dispensable for MPT, although some of these proteins do regulate pore opening (see Halestrap and Richardson, 2014). Evidence favoring interaction between these proteins has been reported for yeast, where VDAC, ANT and PiC can form a complex involved in the channeling of ADP/ATP (Clémençon, 2012), which are known to modulate ScMUC activity (Uribe-Carvajal et al., 2011). However, although we previously favored the possibility that VDAC could at least modulate the pore under specific experimental conditions (Gutiérrez-Aguilar et al., 2007), VDAC has also been largely dismissed as part of the ScMUC/MPT pore componentry (Baines et al., 2007; Krauskopf et al., 2006; Roucou et al., 1997). In mammalian mitochondria, PiC and ANT were proposed to interact with ATP synthase among other proteins (Ko et al., 2003). But some studies have failed to detect such structure in yeast mitochondria (CouohCardel et al., 2010).

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Saccharomyces cerevisiae, three different groups detected a MPT albeit with differing characteristics (Guérin et al., 1994; Jung et al., 1997; Prieto et al., 1995). These groups hypothesized that this transition could be triggered by the opening of a channel termed either the yeast mitochondrial unselective channel (ScMUC) or the yeast mitochondrial permeability transition pore (Manon et al., 1998). The pores in mammalian and S. cerevisiae mitochondria exhibit similar dimensions (Jung et al., 1997) and are regulated by pH and Mg2+ in a similar fashion (Guérin et al., 1994). However, key effectors such as cyclosporine A (CsA) and Ca2+ apparently lack effects on the ScMUC (Jung et al., 1997). This has led to propose that the ScMUC could be considered an inaccurate model for understanding MPT (Manon et al., 1998). Later hypotheses however propose that the MPT pore and the Sc MUC may be more similar than previously thought (Azzolin et al., 2010; Vianello et al., 2012). Evidence also shows that matrix Ca 2 + can open a Ca2+-release pore under appropriate experimental conditions (Carraro et al., 2014; Yamada et al., 2009). Furthermore, we recently found that ScMUC is modulated by ubiquinone derivatives (GutiérrezAguilar et al., 2014b). This family of compounds affects the MPT pore status downstream of cyclophilin D (CypD) regulatory site (Basso et al., 2005; Fontaine et al., 1998a,b). Thus one main difference between the MPT pore and the ScMUC resides on CsA sensitivity. Although CsA potently desensitizes the MPT pore, ScMUC is apparently not modulated by this undecapeptide. Here we examine known structural, regulatory and physiological features of the ScMUC in order to determine whether it shares identity with the MPT pore.

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Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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In 1997, Jung and colleagues evidenced the presence of a CsAinsensitive pore in S. cerevisiae mitochondria. In this work the authors proposed that the failure of CsA to inhibit pore opening in S. cerevisiae mitochondria would not be related to an absence of its target (yeast cyclophilin) or to a failure of CsA to inhibit its isomerase activity. The authors rather supported the possibility that the MPT pore and ScMUC were unrelated entities or that the involvement of cyclophilin in forming or regulating the MPT pore evolved relatively recently. A

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(Uribe-Carvajal et al., 2011). Our group has also tested the effects of the previously described (Kushnareva et al., 1999a) cationic mitochondrial targeting sequence of yeast cytochrome oxidase (CoxIV1–22) on ScMUC activity (Fig. 1). The results show that this peptide can induce the decylubiquinone-sensitive and ScMUC-dependent Δψ drop. In this regard, Szabò and Zoratti have proposed that the identity of the IMM channels responsible for protein import and the MPT pore could coincide (for a recent in-depth review, see Szabò and Zoratti, 2014). These authors also suggest that a possible reason that has led investigators to study both channels as unrelated entities is that the MPT pore has been largely studied in mammalian mitochondria whereas protein import has been substantially characterized in S. cerevisiae. Furthermore, the potential involvement of mitochondrial targeting sequences as inducers of the MPT has been questioned on the basis of decreased sensitivity to canonical MPT modulators such as CsA and EGTA (Kushnareva et al., 2001). Since these molecules suppress pore opening by acting on the matrix side of the inner mitochondrial membrane, it is reasonable to assume that their protective role could be exerted upstream of the mitochondrial signal sequence peptide activation site and consequently their effects would be decreased or inexistent. Sokolove and Kinnally provided evidence for this possibility where 1 μM CsA and 5 mM Mg2+ suppressed CoxIV-induced mitochondrial swelling by 37% and 78.6% respectively (Sokolove and Kinnally, 1996). These authors also determined that mitochondrial targeting sequences, mastoparan and Ca2+/Pi can all induce swelling in mammalian mitochondria with divergent apparent pore size and effector sensitivities, but they also considered the possibility that these activities represent multiple forms of a single multiple-conductance channel (Sokolove and Kinnally, 1996). As recently proposed by Szabò and Zoratti (2014), we also consider that the potential relationship between the mitochondrial protein import machinery and the ScMUC/MTP pore merits further research and validation.

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candidates present in yeast (De Stefani et al., 2011). Mootha's group simultaneously identified the MCU protein through an integrative genomics approach (Baughman et al., 2011) following the previous identification of the MCU regulator MICU1 (Perocchi et al., 2010). The same group has recently used S. cerevisiae to reconstitute the MCU as an endogenous MCU-free model (Kovács-Bogdán et al., 2014). However, the lack of this Ca2+-transporting complex can be bypassed by incubating S. cerevisiae mitochondria with a selective Ca2 + ionophore (ETH129) in the presence of physiological (~1–2 mM) phosphate concentrations. Under such conditions, ScMUC opens in a decavanadateinsensitive fashion (Yamada et al., 2009). This experimental setup also allowed Carraro and colleagues to demonstrate the presence of a phosphate-inhibited, Ca2+-induced Ca2+-release structure in yeast mitochondria incubated with ETH129 plus sequential Ca2+ trains (Carraro et al., 2014). Quite interestingly, Ca2+-release was substantially delayed in mutants lacking ATP synthase subunits e and g. These subunits mediate dimerization of ATP synthase and upon reconstitution in lipid bilayers, the dimers generate channels with multiple conductances, being ~ 300 pS the unit conductance. This conductance represents ~ 25% of the maximal conductance of the mitochondrial megachannel (MMC), which is considered the electrophysiological counterpart of the MPT pore (Kinnally et al., 1991). More recently, von Stockum and colleagues have detected a 53 pS Ca2 +-release channel arising from ATP synthase dimer preparations from Drosophila melanogaster (von Stockum et al., 2014). Based on these studies, Bernardi's group has proposed that the MPT pore forms at the interface between two F0 sectors in the actual inner mitochondrial membrane and that the channel does not depend on the polymeric state of the c-subunit of ATP synthase. This would explain why disparate molecules likely acting at the membrane interphase such as local anesthetics potently inhibit MPT pore opening (Sokolove and Kinnally, 1996). In agreement with this possibility, recent results from Shinohara's group show that the short peptide mastoparan can induce a concentration-dependent, CsA-sensitive or -insensitive mitochondrial permeabilization by interacting with the phospholipid phase of the inner mitochondrial membrane (Yamamoto et al., 2014). In this study, the effects of mastoparan and those of inverso mastoparan, which was synthesized from D-amino acids, were virtually indistinguishable on MPT readings and permeabilization was detected even in phospholipid vesicles. Based on these results, the authors proposed that the MPT pore does not require specific protein receptors at least when induced by cationic peptides. We have previously favored the possibility that the ScMUC can be activated by cationic peptides such as mastoparan

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Fig. 1. The mitochondrial targeting sequence CoxIV1–22 triggers opening of the decylubiquinone-sensitive ScMUC. Peptide additions were a: 1.25 μM, b:2.5 μM, c:5 μM, and d:7.5 μM in the absence (A) or presence (B) of 100 μM decylubiquinone. Changes in fluorescence of 10 μM o-safranine were measured at 495 nmex/586 nmem using an Olis converted SLM AMINCO spectrofluorometer equipped with magnetic stirring and a temperature-controlled water bath (Figueira et al., 2012). Experimental conditions: 0.5 mg mitochondrial protein/mL 0.6 M mannitol, 5 mM MES pH 6.8 (TEA) plus 5 μL/mL 96% ethanol as respiratory substrate. The laboratory strain BY4741 (MATa; his3 Δ1; leu2 Δ0; met15 Δ0; ura3 Δ) was used for this experiment. Representative traces from n = 3.

Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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6. Physiological roles of the ScMUC

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The group of Rial initially proposed that the ScMUC could serve as an ATP-induced energy dissipation valve (Prieto et al., 1996). This hypothesis was based on observations showing that the energetic efficiency of S. cerevisiae correlated inversely with the cytosolic ATP concentration (Grosz and Stephanopoulos, 1990). In a related trend, Manon proposed that the ScMUC is involved in the oxidation of cytosolic NADH without coupling to ATP synthesis. The same group further documented the occurrence of ScMUC opening in situ in a pathway inhibited by 2deoxyglucose (Manon and Guérin, 1998). In this work the authors suggested that the ScMUC could be inhibited in living cells upon ATP depletion. The authors also proposed an important role of this channel in the interaction between mitochondrial and cytosolic metabolism. Rigoulet's group further showed a tight regulation of mitochondrial respiration mediated by glycolytic fructose 1,6-biphosphate (F1,6BP) and glucose 6-phosphate (G6P) in the potential establishment of the Crabtree effect (rapid metabolic change from respiration to fermentation) (Díaz-Ruiz et al., 2008). Our group recently found that the ScMUC is tightly closed by F1,6BP resulting in mitochondrial coupling of oxidative phosphorylation (Rosas-Lemus et al., 2014). Conversely, addition of glucose-6phosphate promotes partial opening of the ScMUC leading to proton leakage across the inner mitochondrial membrane and uncoupling respiration. Based on these observations we propose that the glycolysis intermediates G6P and F1,6BP may contribute to the Crabtree effect in S. cerevisiae by direct modulation of the ScMUC. It would be interesting to test if such intermediates are also able to mediate the Crabtree effect in tumor cells in a MPT pore-dependent context. Partial evidence for this possibility shows at least a direct inhibition of mitochondrial respiration on the respiratory flux of rat liver mitochondria under phosphorylating conditions. Based on these results, it has been suggested that glycolytic intermediates can act as true metabolic messengers by participating in the regulation of the Crabtree effect (Díaz-Ruiz et al., 2008, 2009).

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7. Concluding remarks

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The ScMUC has been hardly considered a canonical counterpart of the MPT for the last 2 decades. However, recent evidence convincingly supports the notion of a conserved MPT pore across many eukaryotic species. The regulation of the ScMUC during the different growing situations of the facultative S. cerevisiae could lead to the discovery of potential physiological roles for this unselective channel. Likewise, it would be interesting to test if such regulatory mechanisms have been conserved in mitochondria from other sources. S. cerevisiae is also an ideal model to gain powerful insight into the structure–function relationships of

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although the CsA-binding domain is remarkably conserved in all cyclophilins, conservation is not evident in the “back” face of the protein (Fig. 2). The “back” face of some cyclophilins usually mediates protein– protein interactions (Reidt et al., 2003; Xu et al., 2006). Another degree of complexity to this system is the fact that the MPT pore sensitivity to CsA varies proportionally with the expression levels of CypD. In other words, CsA insensitivity may also correlate with relative low levels of CypD, as seen in HL60 cells (Li et al., 2012). However, a notable exception to this has been recently reported for the MPT pore of D. melanogaster, where ectopic expression of human CypD results in a sensitized MPT pore to Ca2 + but not to CsA (von Stockum et al., 2014). Another degree of complexity is the divergent role of Pi in pore regulation in mammals and yeast. While Pi displays an inhibitory effect in S. cerevisiae (and Drosophila), in mammals it can act as an inhibitor or activator in a concentration-dependent manner (Kushnareva et al., 1999b), possibly because it alters binding of CypD to the MPT pore/ATP synthase dimers (Giorgio et al., 2013).

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multiple alignment of mitochondrial cyclophilins from diverse species demonstrates this protein in reasonably conserved, however, certain differences could account for its effects on PT (Supplemental Fig. 1). Although a mitochondrial targeting sequence is detected in cyclophilins from Homo sapiens, Mus musculus, Rattus norvegicus, Bos taurus, D. melanogaster, Danio rerio, Neurospora crassa, Debaryomyces hansenii and S. cerevisiae, highly identical cyclophilins from plants such as Triticum aestivum, Solanum tuberosum and Arabidopsis thaliana seem to have a lower probability of import to the mitochondria. In addition, cyclophilin from D. melanogaster appears to have a longer targeting sequence with high probability of import to mitochondria according to the Mitoprot algorithm (0.966) (Claros and Vincens, 1996). However, results by Bernardi's group suggest that this is not the case (von Stockum et al., 2011). S. cerevisiae mitochondrial cyclophilin (protein name CPR3) is known to be involved in the CsA-sensitive processing of imported precursors transported across the protein import complexes of the mitochondrion (Matouschek et al., 1995). As highlighted by Jung et al. (1997), this raises an obligate question: Why is the ScMUC insensitive to CsA, while CPR3-mediated protein processing is still sensitive to the immunosuppressant? A possible answer could be that somehow, yeast CPR3 is not interacting with the ScMUC, whereas other cyclophilins in organisms such as D. rerio, R. norvegicus or M. musculus do interact with their respective pores (for a review see Bernardi and von Stockum, 2012). Studies supporting this possibility show that the S. cerevisiae null mutant for CPR3 does not display significant differences in Ca2+-induced permeability transition, which is a genetic evidence that yeast mitochondrial cyclophilin is not involved in pore regulation (Carraro et al., 2014). Mouse studies reinforcing the notion of a CypD – which is enzymatically active, but not interacting with the MPT pore – show that C203 is critical for the MPT regulation (Nguyen et al., 2011). Upon the mutation of this residue located in the “back” face of CypD (Supplemental Fig. 1), isolated mouse mitochondria behave as a CypD null strain in regard to the pore's calcium and redox sensitivity. In this work, the authors also proposed that the C203S mutation could alter protein–protein interactions between CypD and other MPT pore components. Furthermore, C203 blockade with NO donor GSNO did not affect CypD activity in agreement with a catalytic mechanism whereby the enzyme's CsA-binding domain remains unblocked. An alignment of mitochondrial cyclophilin sequences from diverse species shows that S. cerevisiae CPR3 lacks such conserved cysteine (Supplemental Fig. 1). The absence of this conserved cysteine could suggest why the ScMUC is not sensitive to CsA (Supplemental Figs. 1 and 2). However, a notable exception to this hypothesis is bovine CypD. B. taurus mitochondria support an orthodox MPT response to classic MPT inducers (Hunter and Haworth, 1979; Leung et al., 2008), nonetheless CypD from this source also lacks such regulatory cysteine (Supplemental Fig. 1). Hence, if any CypD cysteine is involved in MPT pore opening, C103 and 133 from M. musculus (which are also absent in S. cerevisiae) could also be critical at least for CypD–MPT pore interactions (Supplemental Fig. 2). The presence of divergent domains on CypD may explain the occurrence of CsA-sensitive and CsA-insensitive MPT pores. Such dissimilarity has also been explained in terms of multiple molecular exaptation events (Vianello et al., 2012). This hypothesis suggests that MPT pores occurred with a similar trait (i.e. CsA sensitivity/insensitivity) and then such trait could have been coopted to perform its current function in diverse organisms. Finally, Bernardi and von Stockum have proposed that the ability of CypD to interact with the MPT pore plausibly occurred later in evolution (Bernardi and von Stockum, 2012). Indeed, the evolutionary history of mitochondrial cyclophilins from the species detailed in Fig. 2A reveals that S. cerevisiae mitochondrial cyclophilin branches divergently compared to mitochondrial cyclophilins from plants, D. rerio and its mammalian counterparts. Protein surface homology comparison between S. cerevisiae cyclophilin versus mitochondrial cyclophilins from the species detailed in Fig. 2A strongly suggests that

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Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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Partially funded by DGAPA/PAPIIT Project IN204015 and CONACyT 239487. M.G.-A. was supported by an American Heart Association Midwest Affiliate Postdoctoral Fellowship (13POST14060013). We acknowledge the excellent technical assistance of Natalia ChiqueteFélix and Ramón Mendez. Mariana C. Valenzuela kindly helped building the figures.

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MPT pores due the capacity of this facultative yeast to grow in the absence of several mitochondrial proteins. Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.mito.2015.04.002.

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Fig. 2. Evolutionary relationships of mitochondrial cyclophilins. (A) The evolutionary history of mitochondrial cyclophilins from Homo sapiens, Mus musculus, Rattus norvegicus, Bos taurus, Drosophila melanogaster, Danio rerio, Triticum aestivum, Solanum tuberosum, Arabidopsis thaliana, Neurospora crassa, Debaryomyces hansenii and Saccharomyces cerevisiae was inferred using the Minimum Evolution method. The optimal tree with the sum of branch length = 1.65684140 is shown. The tree was drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree. The evolutionary distances were computed using the Poisson correction method and are in the units of the number of amino acid substitutions per site. The ME tree was searched using the Close-Neighbor-Interchange (CNI) algorithm at a search level of 0. The neighbor-joining algorithm was used to generate the initial tree. The analysis involved 12 amino acid sequences. All positions containing gaps and missing data were eliminated. There were a total of 163 positions in the final dataset. Evolutionary analyses were conducted in MEGA5 (Tamura et al., 2011). (B) S. cerevisiae mitochondrial cyclophilin homology comparison versus mitochondrial cyclophilins from the species depicted in (A) using ProtSkin (Ritter et al., 2004). High conservation is marked in orange and less conserved domains in white. As expected, homology is remarkably high in the CsAbinding domain (CsA-BD). Conversely, homology is less evident in the “Back” face of CPR3, which is usually involved in protein-protein interactions. S. cerevisiae CPR3 model was generated using I-Tasser (Yang et al., 2014) and rendered using Pymol (The PyMOL Molecular Graphics System, Version 1.5.0.4 Schrödinger, LLC, 2002). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.).

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Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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Please cite this article as: Gutiérrez-Aguilar, M., Uribe-Carvajal, S., The mitochondrial unselective channel in Saccharomyces cerevisiae, Mitochondrion (2015), http://dx.doi.org/10.1016/j.mito.2015.04.002

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The mitochondrial unselective channel in Saccharomyces cerevisiae.

Opening of the mitochondrial permeability transition (MPT) pore mediates the increase in the unselective permeability to ions and small molecules acro...
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