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ScienceDirect Are mitochondria the Achilles’ heel of the Kingdom Fungi? Laurent Chatre and Miria Ricchetti A founding event in the origin of eukaryotes is the acquisition of an extraordinary organelle, the mitochondrion, which contains its own genome. Being linked to energy metabolism, oxidative stress, cell signalling, and cell death, the mitochondrion to a certain extent controls life and death in eukaryotic cells. The large metabolic diversity and living strategies of the Kingdom Fungi make their mitochondria of particular evolutionary interest. The review focuses first on the characteristics of mitochondria in the Kingdom Fungi, then on their implications in the organism survival, pathogenicity and resistance, and finally on proposing unconventional strategies to investigate the biology of fungal mitochondria, unveiling the possibility that mitochondria play as the Achilles’ heel of this kingdom. Addresses Institut Pasteur, Unite´ de Ge´ne´tique Mole´culaire des Levures, CNRS UMR3525 Team Stability of Nuclear and Mitochondrial DNA, 25-28 Rue du Dr. Roux, Paris, France Corresponding author: Chatre, Laurent ([email protected])
cells appeared on the young Earth in the presence of low oxygen and high sulfide levels in the atmosphere and ocean waters [4]. Interestingly, it is suggested that fungi are among the earliest-branching eukaryotes [4]. The Kingdom Fungi includes more than 100 000 described species ranging from multicellular mushrooms to unicellular yeasts [5]. Mitochondria have highly differed in fungi as in other eukaryotes, essentially by distinct loss of the coding content and increased dependence on nuclear factors. Moreover some fungi that live in anoxic environments do not contain mitochondria but carry double-membrane-bound organelles, with no DNA but either the ability to produce ATP generated from pyruvate (hydrogenosomes) or not (mitosomes that seem able to generate iron–sulphur (Fe–S) clusters) [3,6]. In this review are first summarized the characteristics of fungal mitochondria, followed by an overview of implications of mitochondria in fungal physiology, and by the proposal of strategies of investigation aiming to better understand the role of mitochondria in fungal biology.
Current Opinion in Microbiology 2014, 20:49–54 This review comes from a themed issue on Host–microbe interactions: fungi Edited by Jay C Dunlap and Jean Paul Latge´
http://dx.doi.org/10.1016/j.mib.2014.05.001 1369-5274/# 2014 Elsevier Ltd. All rights reserved.
Introduction Eukaryotic cells contain in multiple copies an amazing organelle, the mitochondrion, which originated from the engulfment and progressive transformation of free-living bacteria by another free-living cell. The potential of endosymbiosis for the origin of chloroplasts was first described in 1883 by the French botanist Andreas Franz Schimper, followed by Mereschkowsky in 1905 [1], and became an impactful theory to explain the origin of chloroplasts and mitochondria thanks to Lynn Margulis in 1970 [2]. The proto-mitochondrion likely originated from a a-proteobacteria [1,3]. The next step is currently explained by two alternative models: (1) an obligate aerobe bacteria was engulfed by an anaerobic amitochondrial nucleus-bearing cell host or (2) a facultative anaerobe was engulfed by an archaebacteria-like host cell [1]. This happened in a nearly anaerobic time, between 1.5 and 2.0 billion years ago, in a period where eukaryotic www.sciencedirect.com
Characteristics of mitochondria To date, PubMed-NCBI searches result in 55 564 hits for ‘human mitochondria’, and only about one-fifth and onefourth of hits for ‘plant mitochondria’ and ‘fungi mitochondria’, respectively. In the last category, about twothird of hits concern ‘yeast mitochondria’ and one half ‘Saccharomyces cerevisiae mitochondria’. This rapid overview shows that fungal mitochondria are intensely studied in the budding yeast S. cerevisiae, but much less in other fungal species. Mitochondria are dynamic organelles that range from 0.35 to 1 mm in diameter and are present in almost all eukaryotic cells with few exceptions, like mature red blood cells in mammals. Typically, the double-membrane enclosed mitochondria fuse and divide to generate functional structures ranging from an interconnected tubular network to individual units [7]. A comprehensive view of the heterogeneous mitochondrial morphology and distribution in several fungal species is shown in Figure 1. Mitochondria are central players in the energy metabolism via respiratory chain complexes (Oxidative Phosphorylation or OXPHOS) and in apoptosis [8,9], which plays a role in the development and response to cell damage in higher eukaryotes. In fungi apoptoticlike cell death occurs in response to environmental stress and during ageing, and through factors that display modest conservation compared to the higher eukaryotes counterparts [10]. Mitochondria are also implicated in calcium homeostasis and represent the major source of reactive oxygen species (ROS), which act as signalling molecules but may also generate oxidative stress [11]. Mitochondria carry several copies of their own compact Current Opinion in Microbiology 2014, 20:49–54
50 Host–microbe interactions: fungi
Figure 1
ENVIRONMENTAL YEASTS: ASCOMYCOTA SACCHAROMYCOTINA SACCHAROMYCETES SACCHAROMYCETALES
5 μm Mitochondrial Porin - DAPI Fragmented mitochondrial network
Kuraishia Priceomyces Debaryomyces Starmera Kodamaea Debaryomyces Saccharomyces Metschnikowia Citeromyces capsulata carsonii fabryi amethionina ohmeri tyrocola cerevisiae pulcherrima matritensis
HUMAN PATHOGENIC POLYMORPHIC FUNGUS: Candida albicans ASCOMYCOTA SACCHAROMYCOTINA SACCHAROMYCETES SACCHAROMYCETALES
Yeast
Pseudo-hyphal and hyphal forms Tubular mitochondrial network
form
Clustered mitochondrial network
MitoTracker - DAPI
5 μm
HUMAN PATHOGENIC FILAMENTOUS FUNGUS: Aspergillus fumigatus ASCOMYCOTA PEZIZOMYCOTINA EUROMYCETES EUROTIALES
Conidia
Germinating forms Germination
Fragmented mitochondrial network
MitoTracker - DAPI
5 μm
Tubular mitochondrial network Current Opinion in Microbiology
Mitochondrial morphology and distribution in different fungal species. Note the heterogeneity of mitochondrial morphology from fragmented (diffuse small and big punctuate structures) to clustered and tubular networks. Cells were stained with the mitochondrial marker MitoTracker1 Green FM (Life Technologies) (green) or immunostained with yeast mitochondrial Porin (Life Technologies) (green), and DAPI (Sigma–Aldrich) (blue, nuclei). Highresolution three-dimension confocal acquisition with spinning-disc, 100 objective, 200-nm optical slices and 1.024/1.024 pixels resolution (Imagopole, PFID, Institut Pasteur). 3D reconstruction: IMARIS (Bitplane). Post-acquisition analysis: ImageJ 1.47 K. capsulata, P. carsonii, D. fabryi, S. amethionina, K. ohmeri, D. tyrocola, S. cerevisiae, M. pulcherrima and C. matritensis — generous gifts from Dr. Lucia Morales and Prof. Bernard Dujon, Institut Pasteur; C. albicans — generous gifts from Murielle Chauvel and Dr. Christophe d’Enfert, Institut Pasteur; A. fumigatus — generous gifts from Dr. Vishu Aimanianda and Prof. Jean-Paul Latge´, Institut Pasteur.
double-stranded circular mitochondrial DNA (mtDNA) that is autonomously replicated and transcribed and is mostly dedicated to mitochondrial respiration [12]. Alternative configurations of mitochondrial genomes, which include linear DNAs have been described [6]. Fungal mtDNA range from 19.4 kb (Schizosaccharomyces pombe) to 170 kbp (Agaricus bitorquis). Importantly, the Current Opinion in Microbiology 2014, 20:49–54
mtDNA is associated with proteins to form dynamic mitochondrial nucleoids [12]. Fungal mitochondria display several differences compared to the mitochondria of other organisms. For example, yeasts are facultative anaerobes and can survive without a functional OXPHOS [13]; mtDNA can be found as concatemers in S. cerevisiae [12]; and yeasts Saccharomycetaceae have entirely lost www.sciencedirect.com
Mitochondria the Achilles’ heel of the Kingdom Fungi? Chatre and Ricchetti 51
complex I coding ability in their mtDNA [14]. Complete or partial mtDNA sequences have been found also in the nuclear genome (NUMTs) of the cognate organism. We showed that in S. cerevisiae NUMTs integrate the nuclear genome during the repair of DNA double-strand breaks therein [15]. Moreover, S. cerevisiae NUMTs can act as independent replication origins, and affect the efficiency of other nuclear origins [16]. The nuclear-mitochondrial cross-talk is underscored by the fact that mitochondrial DNA replication, transcription, biogenesis, degradation (mitophagy and mitoptosis), and protein import are under nuclear control [11]. Finally, in addition to the nucleus, mitochondria interact with endoplasmic reticulum (ER), peroxisomes, lysosomes, and plasma membrane [9].
Mitochondria as the maestro of fungal biology Mitochondria are determinant for essential fungal functions and can be considered as the maestro that dictates the fungal biology (Figure 2).
In S. cerevisiae, loss of mitochondrial cytochrome c oxidase induces accumulation of ROS and accelerates senescence due to increased NADPH oxidase (NOX) and decreased antioxidant defence [23]. Interestingly, during P. anserina senescence mitochondria release copper, a chemical element that decreases the expression of the mitochondrial antioxidant Mn-SOD2, and increases the levels of the mainly cytoplasmic Cu/Zn-SOD1 antioxidant [24]. Conversely, copper depletion, which affects the respiratory chain in obligate aerobes, increases the lifespan of this fungus through induction of an alternative oxidase, AOX, a non-energy conserving enzyme of the respiratory chain [24]. Mitochondrial glycerophospholipids and mitochondrial degradation by mitophagy are crucial for lipid homeostasis and lifespan in S. cerevisiae [25,26]. Finally, deletion of the mitochondrial ATPase-associated serine protease CLPP was shown to extend the fungus lifespan by 71%, and complementation by human CLPP reverted this extension [27].
Senescence
Mitochondria play a role in fungi senescence [17], known in higher eukaryotes as an irreversible cell-cycle arrest in response to DNA damage or DNA damage signalling. In 1953, the filamentous fungus Podospora anserina was showed to have a limited lifespan [18]. It was later demonstrated that inhibition of respiration via antibiotics or ethidium bromide prevents senescence of P. anserina [19]. Moreover, senescent cells of P. anserina, Aspergillus amstelodami, and Neurospora crassa accumulate mtDNA rearrangements [20–22], as it is also the case for mtDNA of higher eukaryotes during ageing.
Quiescence
Figure 2
Virulence and pathogenicity Quiescence
Senescence RESPIRATION MITOCHONDRIAL DNA REACTIVE OXYGEN SPECIES COPPER HOMEOSTASIS LIPID HOMEOSTASIS SERINE PROTEASE
RESPIRATION LIPID HOMEOSTASIS
Mitochondria
Virulence & Pathogenicity
Antifungal drug resistance
RESPIRATION MITOCHONDRIAL DNA PROLINE OXIDASE LIPID HOMEOSTASIS CARRIER PROTEIN FUSION
RESPIRATION MITOCHONDRIAL DNA COPPER HOMEOSTASIS LIPID HOMEOSTASIS PHOSPHATASES Current Opinion in Microbiology
Schematic representation of mitochondrial factors and functions implicated in various aspects of fungal biology. www.sciencedirect.com
Mitochondria have been shown to affect fungi quiescence, a reversible cell-cycle arrest characterized by low metabolism and decreased cellular functions, frequently in response to unfavourable environmental conditions [28]. Maintenance of the respiration by coordination of the proteasome with autophagy, which protects against mitochondrial-dependent ROS accumulation, is essential for the survival of quiescent (but not proliferating) fission yeast S. pombe [29,30]. Furthermore, mitochondrial b-oxidation of fatty acid contributes to maintain the viability of quiescent conidia from the filamentous fungus Magnaporthe oryzae [31].
Mitochondria play a role also in the processes by which fungi compete with other organisms for nutrient uptake, and in the activation of pathways for the production of virulence factors and pathogenesis [32–34]. Indeed, disturbance of respiration due to altered iron homeostasis affects the virulence of the yeast Candida albicans [35], and mitochondrial cytochrome c is crucial for Aspergillus fumigatus virulence [36]. Moreover, mtDNA mutations attenuate the virulence of the tree pathogen Cryphonectria parasitica [37] and, importantly, cooperation between mitochondrial genomes controls the virulence of hybrids of the forest pathogen Heterobasidion annosum [38]. Furthermore, mitochondrial proline oxidase, which leads to ROS overproduction and thereby contributes to maintain ROS homeostasis, is essential for the virulence of the human pathogen Cryptococcus neoformans [39]. It has also been showed that mitochondrial b-oxidation of fatty acid is crucial for virulence of C. neoformans and of the maize pathogen Ustilago maydis [40,41]. Finally, the mitochondrial carrier protein FOW1 is required for pathogenicity of the plant pathogen Fusarium oxysporum [42], whereas Current Opinion in Microbiology 2014, 20:49–54
52 Host–microbe interactions: fungi
mitochondrial fusion is associated with hypervirulence of the fatal human pathogen Cryptococcus gattii [43]. Antifungal drug resistance
Mitochondria may also be determinant on a further fungal process, which is necessary for survival, namely the activation of pathways for drug resistance [32–34]. Indeed, the mitochondrial respiratory chain of the yeast pathogen Cryptococcus and the mitochondrial antioxidant Mn-SOD2 of S. cerevisiae plays important roles in drug tolerance [44]. Furthermore, antifungal drugs such as azole and polyene antimycotics can affect the respiration and consequently induce an antifungal drug resistance [32]. Moreover, loss of mtDNA is a key event to promote antifungal drug resistance in yeasts Candida glabrata and S. cerevisiae, which can live without mtDNA. Surprisingly, this is also the case, through a still unclear mechanism, for C. albicans and Cryptococcus spp., which are unable to survive without mtDNA [32]. Furthermore, the copper-induced and mitochondrial-dependent oxidative stress plays a crucial role in drug tolerance in the filamentous fungus Humicola lutea [45]. Importantly, mitochondrial cardiolipin, sphingolipid, and phosphatidylglycerol are key players of antifungal drug resistance, and they also intervene in the resistance to echinocandins that inhibit the cell wall biosynthesis. In this context, lipid homeostasis including for ergosterol, mitochondrial cardiolipin, sphingolipid, and phosphatidylglycerol, and consequently the composition of the plasma membrane and the cell wall are affected by mitochondrial respiration [32]. Finally, mitochondrial phosphatases play an essential role in antifungal drug tolerance in C. albicans [46]. Although far from being complete, this overview underscores how fungal mitochondria play a key role in all the aspects of the life cycle and the ecosystem of this Kingdom. It also discloses that several mitochondrial pathways remain poorly explored although they may provide new cues to understand the biology of the Kingdom Fungi.
Unconventional strategies to investigate fungal mitochondria Aiming to explore differences between host and fungi mitochondria, possibly to select specie-specific targets, we would like to propose several potentially interesting but still poorly explored mitochondrial pathways (Figure 3). (1) Research on copper and iron homeostasis should be emphasised, as well as on calcium homeostasis. Calcium is indeed a key modulator of the respiratory chain, ROS generation, and cell death [47]. Importantly, cytosolic proteins, ER, and mitochondria are the prevalent intracellular storage sites for calcium. Current Opinion in Microbiology 2014, 20:49–54
Figure 3
Calcium homeostasis & ER-Mitochondria interactions
PROPOSED INVESTIGATION STRATEGIES
Sirtuins
Nitroso-redox balance
Mitochondrial proteases
Bacterial-Fungal Interactions (BFIs)
Current Opinion in Microbiology
Summary of proposed strategies to investigate poorly explored pathways aiming to better understand the role of mitochondria in the Kingdom Fungi.
Moreover, mitochondria and ER intimately interact through mitochondria-associated ER membrane for vital functions including calcium buffering, signalling, and cell death [47]. Importantly, specific mitochondria-ER tethers have been found only in the fungal lineage [48]. Thus, deciphering calcium signalling and homeostasis, and mitochondria-ER interactions are promising tracks for distinct fungi and host targeting. (2) Calcium overload not only affects the mitochondrial metabolism, but also leads to generation of ROS and reactive nitrogen species (RNS), which include nitric oxide (NO) through nitric oxide synthases (NOS), and peroxynitrite (ONOO ) when NO interacts with ROS [47]. Mitochondria concentrate dangerous cocktails of NOS, NADPH oxidase (NOX), AOX, ROS, and RNS [49]. The equilibrium between ROS and RNS determines the nitroso-redox balance. The fungal nitroso-redox balance, NOS, NOX, and AOX start to be elucidated in higher eukaryotes, but little is known in fungi. (3) Sirtuins, a family of proteins firstly discovered in yeasts [50], link mitochondrial metabolism and lipid homeostasis. Sirtuins are present in mitochondria, nucleus, and cytosol, and can regulate lifespan, ER stress, metabolism, cell cycle, and DNA repair [50]. Research to modulate fungal sirtuins should focus on mitochondrial lipid homeostasis, mitochondrial respiration, mitophagy, antioxidant defence, mitochondria-nucleus, and mitochondria-ER signalling. (4) Research on mitochondrial proteases. The mitochondrial quality control is mediated by mitochondrial proteases including Lon proteases, m-AAA proteases and i-AAA proteases [51]. Importantly, mitochondrial proteases regulate mitochondrial transcription and translation, mitochondrial metabolism, mitophagy, www.sciencedirect.com
Mitochondria the Achilles’ heel of the Kingdom Fungi? Chatre and Ricchetti 53
mitochondrial lipid homeostasis, and also mitochondrial protein import [51]. (5) The Kingdom Fungi interacts with the other kingdoms. The Bacterial–Fungal Interaction (BFI) is remarkably interesting as it affects key socioeconomical domains including agriculture, food processing, and medicine [52]. BFIs occur via multiple pathways including physiochemical exchanges, chemotaxis, protein secretion, metabolite, and genetic exchanges. BFIs can have profound consequences in all the pathways where mitochondria are key players, meaning a possible impact on fungal survival, pathogenicity, virulence, and antifungal drug tolerance [52]. However, data on the effect of BFIs on mitochondria and, vice versa on the role of mitochondria in promoting BFIs are dramatically missing. Research on the interaction between BFIs and fungal mitochondria should be of crucial interest for the future.
Conclusion Fungal evolution and expansion is a key biological challenge. Additional cues may be available nowadays. As mitochondria are implicated in many aspects of fungal survival, pathogenicity, virulence, and drug resistance, these organelles may represent the Achilles’ heel of the Kingdom Fungi. Here we propose to reinforce the investigation on still poorly explored mitochondrial pathways aiming to better understand the Kingdom Fungi.
Acknowledgements
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We thank Dr. Lucia Morales, Prof. Bernard Dujon, Murielle Chauvel, Dr. Christophe d’Enfert, Dr. Vishu Aimanianda, and Prof. Jean-Paul Latge´ at Institut Pasteur for providing fungi cells analysed in Figure 1. We also thank Prof. Dujon for helpful guidance in the intricate domain of yeast and fungi classification.
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chronologically aging yeast limited in calorie supply sustains functional mitochondria and maintains cellular lipid homeostasis. Aging (Albany, NY) 2013, 5:234-269. This paper shows the complex coordination between distinct mitochondrial mechanisms (calorie restriction, mitophagy, mitochondrial function, lipid homeostasis) to assure long yeast lifespan. 26. Beach A, Richard VR, Leonov A, Burstein MT, Bourque SD, Koupaki O, Juneau M, Feldman R, Iouk T, Titorenko VI: Mitochondrial membrane lipidome defines yeast longevity. Aging (Albany, NY) 2013, 5:551-574. This paper provides evidence that mitochondrial lipid homeostasis is a player in regulating yeast lifespan. 27. Fischer F, Weil A, Hamann A, Osiewacz HD: Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain. Nat Commun 2013, 4:1397. Sixty years after the article of Rizet G., studies on longevity of fungus are still ongoing. This article provides evidences that mitochondrial proteases are of crucial interest for fungus survival. 28. Rittershaus ES, Baek SH, Sassetti CM: The normalcy of dormancy: common themes in microbial quiescence. Cell Host Microbe 2013, 13:643-651. 29. Takeda K, Yanagida M: In quiescence of fission yeast, autophagy and the proteasome collaborate for mitochondrial maintenance and longevity. Autophagy 2010, 6:564-565. 30. De Virgilio C: The essence of yeast quiescence. FEMS Microbiol Rev 2012, 36:306-339. 31. Patkar RN, Ramos-Pamplona M, Gupta AP, Fan Y, Naqvi NI: Mitochondrial beta-oxidation regulates organellar integrity and is necessary for conidial germination and invasive growth in Magnaporthe oryzae. Mol Microbiol 2012, 86:1345-1350.
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ScienceDirect Are mitochondria the Achilles’ heel of the Kingdom Fungi? Laurent Chatre and Miria Ricchetti A founding event in the origin of eukaryotes is the acquisition of an extraordinary organelle, the mitochondrion, which contains its own genome. Being linked to energy metabolism, oxidative stress, cell signalling, and cell death, the mitochondrion to a certain extent controls life and death in eukaryotic cells. The large metabolic diversity and living strategies of the Kingdom Fungi make their mitochondria of particular evolutionary interest. The review focuses first on the characteristics of mitochondria in the Kingdom Fungi, then on their implications in the organism survival, pathogenicity and resistance, and finally on proposing unconventional strategies to investigate the biology of fungal mitochondria, unveiling the possibility that mitochondria play as the Achilles’ heel of this kingdom. Addresses Institut Pasteur, Unite´ de Ge´ne´tique Mole´culaire des Levures, CNRS UMR3525 Team Stability of Nuclear and Mitochondrial DNA, 25-28 Rue du Dr. Roux, Paris, France Corresponding author: Chatre, Laurent ([email protected])
cells appeared on the young Earth in the presence of low oxygen and high sulfide levels in the atmosphere and ocean waters [4]. Interestingly, it is suggested that fungi are among the earliest-branching eukaryotes [4]. The Kingdom Fungi includes more than 100 000 described species ranging from multicellular mushrooms to unicellular yeasts [5]. Mitochondria have highly differed in fungi as in other eukaryotes, essentially by distinct loss of the coding content and increased dependence on nuclear factors. Moreover some fungi that live in anoxic environments do not contain mitochondria but carry double-membrane-bound organelles, with no DNA but either the ability to produce ATP generated from pyruvate (hydrogenosomes) or not (mitosomes that seem able to generate iron–sulphur (Fe–S) clusters) [3,6]. In this review are first summarized the characteristics of fungal mitochondria, followed by an overview of implications of mitochondria in fungal physiology, and by the proposal of strategies of investigation aiming to better understand the role of mitochondria in fungal biology.
Current Opinion in Microbiology 2014, 20:49–54 This review comes from a themed issue on Host–microbe interactions: fungi Edited by Jay C Dunlap and Jean Paul Latge´
http://dx.doi.org/10.1016/j.mib.2014.05.001 1369-5274/# 2014 Elsevier Ltd. All rights reserved.
Introduction Eukaryotic cells contain in multiple copies an amazing organelle, the mitochondrion, which originated from the engulfment and progressive transformation of free-living bacteria by another free-living cell. The potential of endosymbiosis for the origin of chloroplasts was first described in 1883 by the French botanist Andreas Franz Schimper, followed by Mereschkowsky in 1905 [1], and became an impactful theory to explain the origin of chloroplasts and mitochondria thanks to Lynn Margulis in 1970 [2]. The proto-mitochondrion likely originated from a a-proteobacteria [1,3]. The next step is currently explained by two alternative models: (1) an obligate aerobe bacteria was engulfed by an anaerobic amitochondrial nucleus-bearing cell host or (2) a facultative anaerobe was engulfed by an archaebacteria-like host cell [1]. This happened in a nearly anaerobic time, between 1.5 and 2.0 billion years ago, in a period where eukaryotic www.sciencedirect.com
Characteristics of mitochondria To date, PubMed-NCBI searches result in 55 564 hits for ‘human mitochondria’, and only about one-fifth and onefourth of hits for ‘plant mitochondria’ and ‘fungi mitochondria’, respectively. In the last category, about twothird of hits concern ‘yeast mitochondria’ and one half ‘Saccharomyces cerevisiae mitochondria’. This rapid overview shows that fungal mitochondria are intensely studied in the budding yeast S. cerevisiae, but much less in other fungal species. Mitochondria are dynamic organelles that range from 0.35 to 1 mm in diameter and are present in almost all eukaryotic cells with few exceptions, like mature red blood cells in mammals. Typically, the double-membrane enclosed mitochondria fuse and divide to generate functional structures ranging from an interconnected tubular network to individual units [7]. A comprehensive view of the heterogeneous mitochondrial morphology and distribution in several fungal species is shown in Figure 1. Mitochondria are central players in the energy metabolism via respiratory chain complexes (Oxidative Phosphorylation or OXPHOS) and in apoptosis [8,9], which plays a role in the development and response to cell damage in higher eukaryotes. In fungi apoptoticlike cell death occurs in response to environmental stress and during ageing, and through factors that display modest conservation compared to the higher eukaryotes counterparts [10]. Mitochondria are also implicated in calcium homeostasis and represent the major source of reactive oxygen species (ROS), which act as signalling molecules but may also generate oxidative stress [11]. Mitochondria carry several copies of their own compact Current Opinion in Microbiology 2014, 20:49–54
50 Host–microbe interactions: fungi
Figure 1
ENVIRONMENTAL YEASTS: ASCOMYCOTA SACCHAROMYCOTINA SACCHAROMYCETES SACCHAROMYCETALES
5 μm Mitochondrial Porin - DAPI Fragmented mitochondrial network
Kuraishia Priceomyces Debaryomyces Starmera Kodamaea Debaryomyces Saccharomyces Metschnikowia Citeromyces capsulata carsonii fabryi amethionina ohmeri tyrocola cerevisiae pulcherrima matritensis
HUMAN PATHOGENIC POLYMORPHIC FUNGUS: Candida albicans ASCOMYCOTA SACCHAROMYCOTINA SACCHAROMYCETES SACCHAROMYCETALES
Yeast
Pseudo-hyphal and hyphal forms Tubular mitochondrial network
form
Clustered mitochondrial network
MitoTracker - DAPI
5 μm
HUMAN PATHOGENIC FILAMENTOUS FUNGUS: Aspergillus fumigatus ASCOMYCOTA PEZIZOMYCOTINA EUROMYCETES EUROTIALES
Conidia
Germinating forms Germination
Fragmented mitochondrial network
MitoTracker - DAPI
5 μm
Tubular mitochondrial network Current Opinion in Microbiology
Mitochondrial morphology and distribution in different fungal species. Note the heterogeneity of mitochondrial morphology from fragmented (diffuse small and big punctuate structures) to clustered and tubular networks. Cells were stained with the mitochondrial marker MitoTracker1 Green FM (Life Technologies) (green) or immunostained with yeast mitochondrial Porin (Life Technologies) (green), and DAPI (Sigma–Aldrich) (blue, nuclei). Highresolution three-dimension confocal acquisition with spinning-disc, 100 objective, 200-nm optical slices and 1.024/1.024 pixels resolution (Imagopole, PFID, Institut Pasteur). 3D reconstruction: IMARIS (Bitplane). Post-acquisition analysis: ImageJ 1.47 K. capsulata, P. carsonii, D. fabryi, S. amethionina, K. ohmeri, D. tyrocola, S. cerevisiae, M. pulcherrima and C. matritensis — generous gifts from Dr. Lucia Morales and Prof. Bernard Dujon, Institut Pasteur; C. albicans — generous gifts from Murielle Chauvel and Dr. Christophe d’Enfert, Institut Pasteur; A. fumigatus — generous gifts from Dr. Vishu Aimanianda and Prof. Jean-Paul Latge´, Institut Pasteur.
double-stranded circular mitochondrial DNA (mtDNA) that is autonomously replicated and transcribed and is mostly dedicated to mitochondrial respiration [12]. Alternative configurations of mitochondrial genomes, which include linear DNAs have been described [6]. Fungal mtDNA range from 19.4 kb (Schizosaccharomyces pombe) to 170 kbp (Agaricus bitorquis). Importantly, the Current Opinion in Microbiology 2014, 20:49–54
mtDNA is associated with proteins to form dynamic mitochondrial nucleoids [12]. Fungal mitochondria display several differences compared to the mitochondria of other organisms. For example, yeasts are facultative anaerobes and can survive without a functional OXPHOS [13]; mtDNA can be found as concatemers in S. cerevisiae [12]; and yeasts Saccharomycetaceae have entirely lost www.sciencedirect.com
Mitochondria the Achilles’ heel of the Kingdom Fungi? Chatre and Ricchetti 51
complex I coding ability in their mtDNA [14]. Complete or partial mtDNA sequences have been found also in the nuclear genome (NUMTs) of the cognate organism. We showed that in S. cerevisiae NUMTs integrate the nuclear genome during the repair of DNA double-strand breaks therein [15]. Moreover, S. cerevisiae NUMTs can act as independent replication origins, and affect the efficiency of other nuclear origins [16]. The nuclear-mitochondrial cross-talk is underscored by the fact that mitochondrial DNA replication, transcription, biogenesis, degradation (mitophagy and mitoptosis), and protein import are under nuclear control [11]. Finally, in addition to the nucleus, mitochondria interact with endoplasmic reticulum (ER), peroxisomes, lysosomes, and plasma membrane [9].
Mitochondria as the maestro of fungal biology Mitochondria are determinant for essential fungal functions and can be considered as the maestro that dictates the fungal biology (Figure 2).
In S. cerevisiae, loss of mitochondrial cytochrome c oxidase induces accumulation of ROS and accelerates senescence due to increased NADPH oxidase (NOX) and decreased antioxidant defence [23]. Interestingly, during P. anserina senescence mitochondria release copper, a chemical element that decreases the expression of the mitochondrial antioxidant Mn-SOD2, and increases the levels of the mainly cytoplasmic Cu/Zn-SOD1 antioxidant [24]. Conversely, copper depletion, which affects the respiratory chain in obligate aerobes, increases the lifespan of this fungus through induction of an alternative oxidase, AOX, a non-energy conserving enzyme of the respiratory chain [24]. Mitochondrial glycerophospholipids and mitochondrial degradation by mitophagy are crucial for lipid homeostasis and lifespan in S. cerevisiae [25,26]. Finally, deletion of the mitochondrial ATPase-associated serine protease CLPP was shown to extend the fungus lifespan by 71%, and complementation by human CLPP reverted this extension [27].
Senescence
Mitochondria play a role in fungi senescence [17], known in higher eukaryotes as an irreversible cell-cycle arrest in response to DNA damage or DNA damage signalling. In 1953, the filamentous fungus Podospora anserina was showed to have a limited lifespan [18]. It was later demonstrated that inhibition of respiration via antibiotics or ethidium bromide prevents senescence of P. anserina [19]. Moreover, senescent cells of P. anserina, Aspergillus amstelodami, and Neurospora crassa accumulate mtDNA rearrangements [20–22], as it is also the case for mtDNA of higher eukaryotes during ageing.
Quiescence
Figure 2
Virulence and pathogenicity Quiescence
Senescence RESPIRATION MITOCHONDRIAL DNA REACTIVE OXYGEN SPECIES COPPER HOMEOSTASIS LIPID HOMEOSTASIS SERINE PROTEASE
RESPIRATION LIPID HOMEOSTASIS
Mitochondria
Virulence & Pathogenicity
Antifungal drug resistance
RESPIRATION MITOCHONDRIAL DNA PROLINE OXIDASE LIPID HOMEOSTASIS CARRIER PROTEIN FUSION
RESPIRATION MITOCHONDRIAL DNA COPPER HOMEOSTASIS LIPID HOMEOSTASIS PHOSPHATASES Current Opinion in Microbiology
Schematic representation of mitochondrial factors and functions implicated in various aspects of fungal biology. www.sciencedirect.com
Mitochondria have been shown to affect fungi quiescence, a reversible cell-cycle arrest characterized by low metabolism and decreased cellular functions, frequently in response to unfavourable environmental conditions [28]. Maintenance of the respiration by coordination of the proteasome with autophagy, which protects against mitochondrial-dependent ROS accumulation, is essential for the survival of quiescent (but not proliferating) fission yeast S. pombe [29,30]. Furthermore, mitochondrial b-oxidation of fatty acid contributes to maintain the viability of quiescent conidia from the filamentous fungus Magnaporthe oryzae [31].
Mitochondria play a role also in the processes by which fungi compete with other organisms for nutrient uptake, and in the activation of pathways for the production of virulence factors and pathogenesis [32–34]. Indeed, disturbance of respiration due to altered iron homeostasis affects the virulence of the yeast Candida albicans [35], and mitochondrial cytochrome c is crucial for Aspergillus fumigatus virulence [36]. Moreover, mtDNA mutations attenuate the virulence of the tree pathogen Cryphonectria parasitica [37] and, importantly, cooperation between mitochondrial genomes controls the virulence of hybrids of the forest pathogen Heterobasidion annosum [38]. Furthermore, mitochondrial proline oxidase, which leads to ROS overproduction and thereby contributes to maintain ROS homeostasis, is essential for the virulence of the human pathogen Cryptococcus neoformans [39]. It has also been showed that mitochondrial b-oxidation of fatty acid is crucial for virulence of C. neoformans and of the maize pathogen Ustilago maydis [40,41]. Finally, the mitochondrial carrier protein FOW1 is required for pathogenicity of the plant pathogen Fusarium oxysporum [42], whereas Current Opinion in Microbiology 2014, 20:49–54
52 Host–microbe interactions: fungi
mitochondrial fusion is associated with hypervirulence of the fatal human pathogen Cryptococcus gattii [43]. Antifungal drug resistance
Mitochondria may also be determinant on a further fungal process, which is necessary for survival, namely the activation of pathways for drug resistance [32–34]. Indeed, the mitochondrial respiratory chain of the yeast pathogen Cryptococcus and the mitochondrial antioxidant Mn-SOD2 of S. cerevisiae plays important roles in drug tolerance [44]. Furthermore, antifungal drugs such as azole and polyene antimycotics can affect the respiration and consequently induce an antifungal drug resistance [32]. Moreover, loss of mtDNA is a key event to promote antifungal drug resistance in yeasts Candida glabrata and S. cerevisiae, which can live without mtDNA. Surprisingly, this is also the case, through a still unclear mechanism, for C. albicans and Cryptococcus spp., which are unable to survive without mtDNA [32]. Furthermore, the copper-induced and mitochondrial-dependent oxidative stress plays a crucial role in drug tolerance in the filamentous fungus Humicola lutea [45]. Importantly, mitochondrial cardiolipin, sphingolipid, and phosphatidylglycerol are key players of antifungal drug resistance, and they also intervene in the resistance to echinocandins that inhibit the cell wall biosynthesis. In this context, lipid homeostasis including for ergosterol, mitochondrial cardiolipin, sphingolipid, and phosphatidylglycerol, and consequently the composition of the plasma membrane and the cell wall are affected by mitochondrial respiration [32]. Finally, mitochondrial phosphatases play an essential role in antifungal drug tolerance in C. albicans [46]. Although far from being complete, this overview underscores how fungal mitochondria play a key role in all the aspects of the life cycle and the ecosystem of this Kingdom. It also discloses that several mitochondrial pathways remain poorly explored although they may provide new cues to understand the biology of the Kingdom Fungi.
Unconventional strategies to investigate fungal mitochondria Aiming to explore differences between host and fungi mitochondria, possibly to select specie-specific targets, we would like to propose several potentially interesting but still poorly explored mitochondrial pathways (Figure 3). (1) Research on copper and iron homeostasis should be emphasised, as well as on calcium homeostasis. Calcium is indeed a key modulator of the respiratory chain, ROS generation, and cell death [47]. Importantly, cytosolic proteins, ER, and mitochondria are the prevalent intracellular storage sites for calcium. Current Opinion in Microbiology 2014, 20:49–54
Figure 3
Calcium homeostasis & ER-Mitochondria interactions
PROPOSED INVESTIGATION STRATEGIES
Sirtuins
Nitroso-redox balance
Mitochondrial proteases
Bacterial-Fungal Interactions (BFIs)
Current Opinion in Microbiology
Summary of proposed strategies to investigate poorly explored pathways aiming to better understand the role of mitochondria in the Kingdom Fungi.
Moreover, mitochondria and ER intimately interact through mitochondria-associated ER membrane for vital functions including calcium buffering, signalling, and cell death [47]. Importantly, specific mitochondria-ER tethers have been found only in the fungal lineage [48]. Thus, deciphering calcium signalling and homeostasis, and mitochondria-ER interactions are promising tracks for distinct fungi and host targeting. (2) Calcium overload not only affects the mitochondrial metabolism, but also leads to generation of ROS and reactive nitrogen species (RNS), which include nitric oxide (NO) through nitric oxide synthases (NOS), and peroxynitrite (ONOO ) when NO interacts with ROS [47]. Mitochondria concentrate dangerous cocktails of NOS, NADPH oxidase (NOX), AOX, ROS, and RNS [49]. The equilibrium between ROS and RNS determines the nitroso-redox balance. The fungal nitroso-redox balance, NOS, NOX, and AOX start to be elucidated in higher eukaryotes, but little is known in fungi. (3) Sirtuins, a family of proteins firstly discovered in yeasts [50], link mitochondrial metabolism and lipid homeostasis. Sirtuins are present in mitochondria, nucleus, and cytosol, and can regulate lifespan, ER stress, metabolism, cell cycle, and DNA repair [50]. Research to modulate fungal sirtuins should focus on mitochondrial lipid homeostasis, mitochondrial respiration, mitophagy, antioxidant defence, mitochondria-nucleus, and mitochondria-ER signalling. (4) Research on mitochondrial proteases. The mitochondrial quality control is mediated by mitochondrial proteases including Lon proteases, m-AAA proteases and i-AAA proteases [51]. Importantly, mitochondrial proteases regulate mitochondrial transcription and translation, mitochondrial metabolism, mitophagy, www.sciencedirect.com
Mitochondria the Achilles’ heel of the Kingdom Fungi? Chatre and Ricchetti 53
mitochondrial lipid homeostasis, and also mitochondrial protein import [51]. (5) The Kingdom Fungi interacts with the other kingdoms. The Bacterial–Fungal Interaction (BFI) is remarkably interesting as it affects key socioeconomical domains including agriculture, food processing, and medicine [52]. BFIs occur via multiple pathways including physiochemical exchanges, chemotaxis, protein secretion, metabolite, and genetic exchanges. BFIs can have profound consequences in all the pathways where mitochondria are key players, meaning a possible impact on fungal survival, pathogenicity, virulence, and antifungal drug tolerance [52]. However, data on the effect of BFIs on mitochondria and, vice versa on the role of mitochondria in promoting BFIs are dramatically missing. Research on the interaction between BFIs and fungal mitochondria should be of crucial interest for the future.
Conclusion Fungal evolution and expansion is a key biological challenge. Additional cues may be available nowadays. As mitochondria are implicated in many aspects of fungal survival, pathogenicity, virulence, and drug resistance, these organelles may represent the Achilles’ heel of the Kingdom Fungi. Here we propose to reinforce the investigation on still poorly explored mitochondrial pathways aiming to better understand the Kingdom Fungi.
Acknowledgements
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