Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics

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Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics夽

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Sarah Foriela , Peter Willemsb , Jan Smeitinka,d , Annette Schenckc , Julien Beyratha,∗ a

Khondrion BV, Nijmegen, The Netherlands Department of Biochemistry (286), NCMD, Radboud University Medical Center, Nijmegen, The Netherlands Department of Human Genetics (855), Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands d Department of Pediatrics, NCMD, Radboud University Medical Center, Nijmegen, The Netherlands b c

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Article history: Received 26 November 2014 Received in revised form 19 January 2015 Accepted 29 January 2015 Available online xxx

This article is part of a Directed Issue entitled: Mitochondrial Diseases. © 2015 Published by Elsevier Ltd.

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Keywords: Mitochondrial disease OxPhos deficiency Drug target discovery Drosophila melanogaster Model organism

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1. Background

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While often presented as a single entity, mitochondrial diseases comprise a wide range of clinical, biochemical and genetic heterogeneous disorders. Among them, defects in the process of oxidative phosphorylation are the most prevalent. Despite intense research efforts, patients are still without effective treatment. An important part of the development of new therapeutics relies on predictive models of the pathology in order to assess their therapeutic potential. Since mitochondrial diseases are a heterogeneous group of progressive multisystemic disorders that can affect any organ at

Abbreviations: OxPhos, oxidative phosphorylation system; CI, Complex I or NADH: ubiquinone oxidoreductase; CII, Complex II or succinate: ubiquinone oxidoreductase; CIII, Complex III or ubiquinol: cytochrome c oxidoreductase; CIV, Complex IV or cytochrome c oxidase; CV, Complex V or F0 -F1 ATP synthase; ATP, adenosine triphosphate; mtDNA, mitochondrial Deoxyribonucleic acid; ROS, reactive oxygen species; UAS, upstream activating sequence; GAL4, galactose yeast transcriptional activator; CRISP, clustered regularly interspaced short palindromic repeats; Cas9, caspase 9; TALEN, Transcription activator-like effector nucleases; tko, technical knockout; TALEN, Transcription activator-like effector nucleases; FRDA, Friedreich ataxia; NDUFS, NADH dehydrogenase (ubiquinone) Fe-S protein; MB, methylene blue. 夽 This article is part of a Directed Issue entitled: Mitochondrial Diseases. ∗ Corresponding author. Tel.: +31 24 3617505. E-mail address: [email protected] (J. Beyrath).

• Mitochondrial diseases as a group belong to the most frequent inborn errors of metabolism. • Patients with life-threatening mitochondrial diseases are without effective treatments. • Mitochondrial diseases are genetically and phenotypically highly heterogeneous. • The rarity of individual mitochondrial diseases and their phenotypic variability has greatly hampered drug development. • Mitochondrial diseases can be modeled in Drosophila, an exceptionally efficient and versatile alternative animal model. • Various Drosophila outcome measures can be used to screen compound collections in various models at a time.

any time, the development of various in vivo models for the different diseases-associated genes defects will accelerate the search for effective therapeutics. Here, we review existing Drosophila melanogaster models for Q3 mitochondrial diseases, with a focus on alterations in oxidative phosphorylation, and discuss the potential of this powerful model organism in the process of drug target discovery.

http://dx.doi.org/10.1016/j.biocel.2015.01.024 1357-2725/© 2015 Published by Elsevier Ltd.

Please cite this article in press as: Foriel S, et al. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.024

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Mitochondrial diseases, while often regarded as a single entity, comprise a wide range of distinct clinical entities (Koopman et al., 2012). When taken as a whole, mitochondrial disorders are one of the most frequent categories of inborn errors of metabolism, with an incidence estimated of 1 in 5000 individuals (Smeitink et al., 2001). Associated with severe and an extreme variety of clinical symptoms, mitochondrial diseases can lead to substantial morbidity and premature death. There are currently no treatments available. Among mitochondrial disorders, defects in the oxidative phosphorylation (OxPhos) system are the most prevalent. This system consists of five multi-subunit complexes (CI–CV) generating the high-energy phosphate molecule adenosine triphosphate (ATP) through a series of complex biochemical processes (Distelmaier et al., 2009; Koopman et al., 2013). The subunits forming the five complexes are encoded by either the nuclear or mitochondrial DNAs (mtDNA) and are therefore potential targets to mutations in both genomes (Smeitink et al., 2001). It is still unclear how cells and tissues become dysfunctional in response to isolated or combined OxPhos deficiencies. Potential obvious cellular pathomechanisms are insufficient ATP production, increased reactive oxygen species (ROS) production, corrupted mitochondrial membrane potential, and calcium homeostasis, but also the alteration of other indispensable cellular processes such as the mitochondrial pathways of cell death (Tait and Green, 2012). All together, these cellular defects lead to devastating multisystemic symptoms affecting different organs. Successful drug development relies, among other parameters, on a deep understanding of the underlying molecular and cellular mechanisms that can be targeted pharmacologically, and on the availability of predictive models to assay the potential responsiveness of patients to a new therapeutic approach. In this context, in vivo models of diseases represent critical tools to test outcome measures that are of direct relevance for complex multisystemic diseases such as mitochondrial disorders, reflecting the organizational and biological features of the different host tissues or the organism as a whole. Testing potential treatment strategies on various in vivo models recapitulating the clinical and/or molecular variability observed in the different mitochondrial diseases can increase (1) the knowledge about specific mechanisms causing the different syndromes, and (2) the success rate during clinical trial phases by enabling stratification of patients based on their potential responsiveness toward a specific therapeutic. Therefore, the development of a comprehensive collection of complementary animal models is crucial to expedite the search for new treatment for mitochondrial diseases. Since there are only a limited number of mouse models for mitochondrial diseases, the fruit fly Drosophila melanogaster represents an attractive alternative (Fig. 1). Here, we have reviewed the literature about existing Drosophila models for mitochondrial disorders, and discuss their potential use and predictive power, to evaluate new potential therapeutics as an initial step in the drug identification process. The list of advantages to use Drosophila is long: a short life cycle, a high reproduction rate, easy maintenance of cultures and molecular systems with conserved cellular and physiological function, and less functional redundancies compared to mammals. Nearly 75% of disease-related genes in humans have functional orthologs in Drosophila (Reiter et al., 2001; Van der Voet et al., 2014). The genes encoding the OxPhos complexes are highly conserved from Drosophila to human (Sardiello, 2003; Jacobs et al., 2004; Tripoli et al., 2005), and so are genes encoding enzymes involved OxPhos-related processes such as ROS scavenging (Anderson et al., 2008; Angeles et al., 2014). Like in mammals, muscle fibers can be either glycolytic or oxidative (Piccirillo et al., 2014). Together, this strengthens the validity of Drosophila melanogaster as a model for

mitochondrial disorders and more specifically for OxPhos deficiencies. The power of Drosophila as a model surely resides in the massive available resources, toolboxes, and powerful genetics that enable manipulation of expression of, in principle, any gene of interest in spatiotemporal pattern of choice (Matthews et al., 2005; Dietzl et al., 2007; Venken and Bellen, 2014). Due to the advantages of Drosophila, many models for mitochondrial genes deficiencies can thus be generated at reasonable time and costs when compared to mammalian models. The UAS–Gal4 system developed by Brand and Perrimon in 1993 is assuredly one of the powerful tools to flexibly modulate gene expression. This system allows the expression of a transgene in a spatially and temporally controlled manner. The temperature-sensitivity of the system moreover allows, when combined with genome-wide resources of RNA interference (Dietzl et al., 2007), to decrease the level of expression of any gene in a tightly controlled manner. Therefore, while knockout or strong knockdown of a specific gene can lead to early lethality not suitable for drug testing, conditional or mild knockdown allows the investigator to tune the level of expression in order to obtain a suitable phenotype–outcome measure. Classic genetic mutants can be obtained by forward mutagenesis and complementation screening, imprecise P-element excision mutagenesis, and homologous recombination strategies. The latter can also be used to exchange wildtype proteins against their mutant versions. These methodologies, among others, have been used to target and modulate expression of mitochondrial genes in Drosophila. The different models reported in the literature are listed in Tables 1 and 2. It can be anticipated that recent methods for genome editing, such as the CRISPR/Cas9 system (Gratz et al., 2013) and TALENs technology enabling directed point mutations (Liu et al., 2012, 2014; Beumer and Carroll, 2014) will further facilitate generation of disease models reflecting the defects found in patients suffering from mitochondrial diseases even closer. The power of a disease model lies in its capability to recapitulate the specific aspects of a particular human pathology, at the different level of complexity, from molecules to organism. Although the number of Drosophila models for mitochondrial disorders is still rather low, those already existing confirm their overall great potential. The fly mutant technical knockout (TKO) carries a point mutation (L85H) in the gene for the mitoribosomal protein S12 involved in the mitochondrial protein synthesis machinery, leading to a deficiency of mitochondrial translational capacity. The TKO flies display biochemical defects such as decreased OxPhos capacity, with reduced activity of CI, CIII, and CIV, and impaired ATP synthesis, which are key molecular features in patient suffering from mutation in the mitochondrial protein synthesis apparatus (Jacobs et al., 2004). Interestingly, the model also exhibits a defective response to sound (Toivonen et al., 2001). As sensorineural deafness is a common pathological states encounter in patients with mutations in mtDNA, the TKO fly represents a valid model for mitochondrial hearing loss. A number of models for OxPhos complexes deficiencies have already been reported (Table 1). They often exhibit common phenotypic features, although with different levels of severity, such as shortened lifespan or lethality, developmental delay, muscle weakness, neuronal dysfunction and degeneration, seizures, and a decreased activity of the specific targeted complex, all of which are phenotypes commonly observed in patients. In Drosophila, multiple techniques and assays are available to assess these and related systemic defects, such as locomotors tests (e.g., monitoring of activity and movements, flight, and climbing assays) (Walker et al., 2006; Fernandez-Ayala et al., 2009; Ghezzi et al., 2011), electrophysiological and morphological investigations of neurons (which due to the ease of accessibility are often applied to the Drosophila eye and photoreceptors as neuronal models) (Van Bon et al., 2013), and bang

Please cite this article in press as: Foriel S, et al. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.024

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Fig. 1. Strategies to screen new therapeutics in Drosophila models of OxPhos deficiencies. Drosophila melanogaster models can play an important intermediate role in the therapeutic development process and are expected to enable the identification of new therapeutics.

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sensitivity tests (seizures) (Royden et al., 1987; Zhang et al., 1999; Vartiainen et al., 2014). Mutations in the human mitochondrial ATP6 gene, an essential component of the F1 F0 -ATP synthase cause devastating multisystem disorders. The fly mutant ATP6 displays muscle pathology and neurodegeneration reminiscent of abnormalities associated with human NARP (neuropathy, ataxia, and retinis pigmentosa), MILS (maternally inherited Leigh’s syndrome), and FBSN (familial bilateral striatal necrosis), but also impaired CV activity, abnormal mitochondrial inner membrane structure (Celotto and Frank, 2006; Palladino, 2010). Altogether, those examples confirm the potential of Drosophila to recapitulate specific phenotypes observed in patients. We believe that Drosophila melanogaster also holds promises for the assessment of potentially therapeutic compounds and the identification of drug targets. While the pharmacokinetics of the drug may be distinct from that occurring in mammals, it nevertheless, provides additional, if not higher qualitative information than in vitro or cellular drug screening, such as oral availability, metabolic stability, or toxicity of a drug. The latter has been shown to be highly correlated between human and Drosophila (Rand, 2010). Drosophila has all of the major cell-types and structures that perform the equivalent functions of the mammalian main organs affected by mitochondrial disorders. Furthermore, Drosophila shares similar signaling molecular pathways and cellular processes that can be targeted pharmacologically. For instance, some molecular and cellular signaling pathways leading to neurodegeneration are common to fly and humans. Effects of certain drugs targeting the central nervous system have been shown to overlap in the two species (Stilwell et al., 2006). Since neurological defects are a major and common clinical aspect of mitochondrial OxPhos diseases, Drosophila models have a high validity for drug target discovery. Whereas numerous genetic abnormalities of mitochondria in human diseases are known, there is a striking absence of identified causative molecular and cellular pathways linked to the mitochondria that could be targeted pharmacologically. Therefore, identification of effective compounds by screening libraries of pharmacologically active substances would greatly accelerate identification of therapeutic targets, and pave the way to find treatment for mitochondrial disorders (Fig. 1). Drosophila has recently been used for in vivo compound screening in the field of cancer

and Alzheimer’s disease using 96-well plates template, leading to identification of quality hit compounds (Gladstone and Su, 2011; McKoy et al., 2012; Willoughby et al., 2013). Although, still far from the number of compounds tested in an in vitro high-throughput screen (100,000), it is reasonable to aim at testing 100–1000 compounds per month, depending on the outcome measures and to which degree it can be automated. Drosophila can also be used to identify genetic modifiers, molecular pathways, and mechanisms that underlie disease symptoms, through testing for genetic interaction (e.g., synthetic lethality or modification of other phenotypes) (Rand et al., 2006; Cox and Spradling, 2009). As already stated by others, “a respiratory-chain deficiency can theoretically give rise to any symptom, in any organ or tissue, at any age, and with any mode of inheritance” (Munnich et al., 1996). It is, therefore, difficult to draw links between mutated genes, causative molecular mechanisms, and clinical alterations within the heterogeneous group of mitochondrial disorders. As an example, while mutations in the different 44 subunits composing the OxPhos complex I often cause a reduction in its activity, they can lead to a large spectrum of symptoms. This highlights the potential involvement of different causative molecular mechanisms downstream of complex I inhibition. In addition, reduced activity of complex I has been associated with other diseases, such as Parkinson’s disease (Vos et al., 2012; Morais et al., 2009, 2014; Pogson et al., 2014), Alzheimer’s disease, or Friedreich’s ataxia (FRDA), broadening the number of potential pathomechanisms linked to CI inhibition. In this context, parallel screening of a library of recognized pharmacologically active substances on different mitochondrial models of complex I deficiencies would help to understand the link between a specific gene or mutation, and the disease-causative molecular mechanisms. Recently, a Drosophila model of FRDA was shown to recapitulate heart dilatation, systolic and diastolic perturbations observed in the patients (Tricoire et al., 2014). In order to elucidate whether the impairment in the OxPhos complexes activity was responsible for the heart dilatation symptom, the authors developed Drosophila models for CI deficiency, by knocking down the CI subunits NDUFS2, NDUFS7 (CI core subunits), and NDUFC2. Despite some minor differences in the phenotypes studied, the three models confirmed the implication of reduced complex I activity in the heart dilatation feature. More interestingly, the responsiveness of the three lines toward the drug methylene blue (MB), an electron carrier, was different. MB could

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Table 1 Genetically modified and induction Drosophila melanogaster models for mitochondrial OxPhos proteins. OxPhos complex

Human gene

Fly symbol and ID

Tissue targeted

Methodology

References

Complex I (NADH: ubiquinone oxidoreductase)

NDUFS1

ND-75 (CG2286)

Ubiquitous, neuronal and glia specific

UAS/GAL4

Hegde et al., 2014

NDUFS2 NDUFC2 NDUFS7 NDUFS3

ND-49 (CG1970) ND-B14.5B (CG12400) ND-20 (CG9172) ND-30 (CG12079)

Heart specific

UAS/GAL4

Tricoire et al., 2014

Ubiquitous

NDUFS3 NDUFB1 MT-ND2

ND-30 (CG12079) ND-MNLL (CG18624) mt:ND2 (CG34063)

Ubiquitous

Mutant through P-element excision UAS/GAL4

Li et al. 2013 (Abstract ASGH) Vos et al., 2012 Burman et al. 2014

NDUFAF1

CIA30 (CG7598)

Ubiquitous

NDUFAF6/ C8orf38 NDUFA10

Sicily (CG15738)

Ubiquitous

ND-42 (CG6343)

Targeted mtDNA mutation using restriction enzyme 3 nt insertion (ND2ins1 ) and 9 nt deletion (ND2del1 ) P element insertion dCIA30EY09101 or excision dCIA30ex80 or UAS/GAL4 Mutants SicilyE (nonsense mutation) and SicilyC (deletion)

SDHB

SdhB (CG3283)

Ubiquitous

SDHAF3

Sdhaf3 (CG14898)

Ubiquitous

SDHAF4 PDSS1

Sirup (CG7224) Qless (CG31005)

Ubiquitous Ubiquitous

TTC19

Ttc19 (CG15173)

Ubiquitous

UQCR10

Oxen/QCR9 (CG8764)

Ubiquitous

COX4I2 COX5B

COX4 (CG10664) COX5B (CG11015)

Ubiquitous

COX4I2 COX5A COX5B COX6A COX6B COX6C COX7A SURF1 COX6A

COX4 (CG10664), COX5A (CG14724), COX5B (CG11015), levy (CG17280), COX6B (CG14235), cype (CG14028), COX7A (CG9603), Surf1 (CG9943) Levy (CG17280)

Ubiquitous, nervous system and/or muscle specific

UAS/GAL4

Kemppainen et al., 2014

Ubiquitous

Liu et al. 2007

SURF1

Surf1 (CG9943)

SCO1/SCO2 CEP8

Scox (CG8885) Cep89 (CG8214)

Mutant P-element excision UAS/GAL4

Porcelli et al. 2010 van Bon et al. 2013

MT-ATP6

Mt-ATPase6 (CG34073)

Ubiquitous, central nervous system, muscle or mesoderm specfic Ubiquitous Ubiquitous, muscles, neurons, wing and eye specific Ubiquitous

Ethyl methane sulfonate-induced mutation UAS/GAL4

ATP5F1

ATPsynb (CG8189)

Endogenous missense mutation UAS/GAL4

Celotto and Frank, 2006; Palladino, 2010 Chen et al. 2014

ATP5H

ATPsynD (CG6030)

UAS/GAL4

Sun et al. 2014

Complex II Succinate dehydrogenase

Coenzyme Q Complex III (ubiquinolcytochrome c reductase)

Complex IV Cytochrome c oxidase

Complex V ATP synthase

Homoplasmy ubiquitous

UAS/GAL4 P-element insertion sdhBEY12081 mutant or deletion sdhBex66 Mutant (gene targeting null mutation) Mutant Ethyl methane sulfonate-induced mutation PiggyBAC element insertion or UAS/GAL4

Mutant P-element insertion and excision UAS/GAL4

Ubiquitous and testis specific Ubiquitous

Cho et al. 2012

Zhang et al. 2013

Walker et al., 2006

Na et al. 2014 Van Vranken et al. 2014 Grant et al. 2010 Ghezzi et al., 2011

Frolov et al. 2000 Klichko et al. 2014

Da-Re et al. 2014

Abbreviations: NDUFS, NADH dehydrogenase (ubiquinone) Fe–S protein; UAS, upstream activating sequence; GAL4, galactose yeast transcriptional activator; MT-ND, mitochondrially encoded NADH dehydrogenase; C8orf38, chromosome 8 open reading frame 38; SDH, succinate dehydrogenase; SURF1, surfeit locus protein 1; CEP89, centrosomal protein 89 kDa.

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totally or partially restore the phenotype in NDUFS7 and NDUFC2, respectively, while it had no effect in the NDUFS2 knockdown flies (Tricoire et al., 2014). This observation highlights that even shared symptoms observed in different models of mitochondrial deficiencies might originate from alteration of different molecular mechanisms downstream of a common CI deficiency, a crucial

factor in drug reversibility. Ultimately, it illustrates that not all patients with mutations in subunits of complex I will benefit from the same treatment. Similarly, while the phenotypes of fly models for two different mitochondrial proteins, the tko25t and the sesB1 (a mutant allele of the Adenine Nucleotide Translocase) largely overlap (Vartiainen et al., 2014), only one could be rescued by the

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Table 2 Genetically modified and induction Drosophila melanogaster models for proteins associated with mitochondrial functions. Targeted gene symbol (annotation)

Human gene symbol and name

Associated function

Targeted tissue

Methodology

References

Tko (CG7925)

MRPS12 Mitochondrial Ribosomal Protein S12

Mitochondrial protein synthesis

Ubiquitous

Mutant L85H

DNApol-␥35 (CG33650)

POLG DNA Polymerase gamma

mtDNA replication

Ubiquitous

Drp1 (CG3210)

DRP1 Dynamin-related protein 1 MFN2 Mitofusin 2

Mitochondria fission

Ubiquitous

Mutant pol ␥ˇ1/ˇ2 and tam3 /tam9 Mutant

Royden et al., 1987; Toivonen et al., 2001; Jacobs et al., 2004 Baqri et al. 2009

Mitochondria fusion

Ubiquitous or heart

UAS/GAL4

OPA1 Optic atrophy 1 SOD1 Superoxide dismutase 1

Mitochondria shaping

Heart

UAS/GAL4

Cytosolic antioxidant enzyme

Ubiquitous

Ethyl methane sulfonate-induced mutation UAS/GAL4

Phillips and Campbell 1989

UAS/GAL4

Kirby and Hu 2002

Recessive missense mutation Mutant P-element insertion UAS/GAL4 Mutant P-element excision Mutant P-element excision

Celotto et al. 2012

Marf (CG3869)

Opa1 (CG8479) Sod (CG11793)

Sod2 (CG8905)

SOD2 Superoxide dismutase 2

Mitochondrial antioxidant enzyme

Neurons, glia or muscles Ubiquitous

Acon (CG9244)

ACON Aconitase

TCA cycle

Ubiquitous

Taz (CG8766)

TAZ Tafazzin VDAC Voltage-dependent anion channel ANT1 Adenine nucleotide translocase type 1

Cardiolipin metabolism

Ubiquitous

Metabolites transport

Ubiquitous

Metabolites transport

Ubiquitous

Porin (CG6647)

SesB (CG16944)

Mutant

Verstreken et al. 2005 Dorn et al. 2011; Debattisti and Scorrano 2013

Cheng et al. 2013

Xu et al. 2006 Graham et al. 2010

Zhang et al., 1999; Vartiainen et al., 2014

Abbreviations: MARF, mitochondrial assembly regulatory factor.

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somatic expression of an alternative oxidase (Kemppainen et al., 2014). The large repertoire of Drosophila models that can be generated can therefore provide crucial information for the development of personalized medicine.

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2. Conclusion

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The need of therapeutics for mitochondrial diseases is a main concern and to achieve this goal, innovative and complementary animal models are required. Drosophila is increasingly used to model human diseases and it was convincingly shown that existing models recapitulate specific phenotypic aberration observed in patients suffering from mitochondrial diseases. While Drosophila as an invertebrate has obvious limitations when compared to mammalian models, it represents an attractive alternative model in the early drug target discovery process for mitochondrial diseases.

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Acknowledgements

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This work was supported by the Marie-Curie Initial Training Networks (ITN) grant MEET (Mitochondrial European Educational 287 Training (FP7-PEOPLE-2012-ITN Grant Agreement no.317433), a 288 PM-Rare (Priority Medicines Rare disorders and orphan diseases) 289 grant from the Netherlands Organization for Health Research and 290 Development-Medical Sciences (No: 40-41900-98-033) and the 291 Q5 Energy4All foundation (www.energy4all.nl). 292 Q4 286

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Please cite this article in press as: Foriel S, et al. Mitochondrial diseases: Drosophila melanogaster as a model to evaluate potential therapeutics. Int J Biochem Cell Biol (2015), http://dx.doi.org/10.1016/j.biocel.2015.01.024

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