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Mitosomes in Entamoeba Histolytica Contain a Sulfate Activation Pathway

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Mitosomes in Entamoeba Histolytica Contain a Sulfate Activation Pathway Mitosomes in Entamoeba histolytica contain a sulfate activation pathway Fumika Mi-ichi, Mohammad Abu Yousuf, Kumiko Nakada-Tsukui, and Tomoyoshi Nozaki1 Department of Parasitology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan Edited by Andrew Roger, Dalhousie University, Halifax, NS, Canada, and accepted by the Editorial Board October 19, 2009 (received for review June 25, 2009) Hydrogenosomes and mitosomes are mitochondrion-related or- and M. balamuthi lack the ISC system, and instead possess the ganelles in anaerobic/microaerophilic eukaryotes with highly re- nitrogen fixation (NIF) system, which is most likely derived from an duced and divergent functions. The full diversity of their content ancestral nitrogen fixing ␧-proteobacterium by lateral gene transfer and function, however, has not been fully determined. To under- (22, 24). Only 5 proteins have been demonstrated in E. histolytica stand the central role of mitosomes in Entamoeba histolytica,a mitosomes: Cpn60 (8–10, 12), Cpn10 (13), mitochondrial Hsp70 parasitic protozoon that causes amoebic dysentery and liver ab- (11, 15), pyridine nucleotide transhydrogenase (PNT) (2, 8), and scesses, we examined the proteomic profile of purified mitosomes. mitochondria carrier family (MCF, ADP/ATP transporter) (14), Using 2 discontinuous Percoll gradient centrifugation and MS and the central role of mitosomes in E. histolytica remains unknown. analysis, we identified 95 putative mitosomal proteins. Immuno- Analysis of the genome of E. histolytica has not revealed any fluorescence assay showed that 3 proteins involved in sulfate additional information regarding the function of mitosomes and activation, ATP sulfurylase, APS kinase, and inorganic pyrophos- thus, a proteomic analysis of mitosomes seems to be the best phatase, as well as sodium/sulfate symporter, involved in sulfate approach to understand its structure and function (1, 2). uptake, were compartmentalized to mitosomes. We have also In this study, we examined the proteomic profile of purified provided biochemical evidence that activated sulfate deriva- mitosomes and showed by immunofluorescence assay that a rep- tives, adenosine-5؅-phosphosulfate and 3؅-phosphoadenosine-5؅- ertoire of proteins were localized to mitosomes, and demonstrated phosphosulfate, were produced in mitosomes. Phylogenetic anal- by enzymological studies that some of these mitosomal proteins EVOLUTION ysis showed that the aforementioned proteins and chaperones were associated with sulfate activation. We further showed by have distinct origins, suggesting the mosaic character of mito- phylogenetic analysis that mitosomes are a mosaic organelle con- somes in E. histolytica consisting of proteins derived from ␣- sisting of components derived from at least 3 distinct origins. This proteobacterial, ␦-proteobacterial, and ancestral eukaryotic ori- study identifies that sulfate activation is the major function of gins. These results suggest that sulfate activation is the major mitosomes in E. histolytica. function of mitosomes in E. histolytica and that E. histolytica mitosomes represent a unique mitochondrion-related organelle Results with remarkable diversity. Identification of Mitosomal Proteins. To elucidate the central role of mitosomes in E. histolytica, we took a proteomic approach to anaerobic protozoa ͉ evolution ͉ mitochondria ͉ organelle ͉ proteomics identify the proteins associated with mitosomes. We developed an improved purification scheme, consisting of 2 consecutive discon- iversification of mitochondrial structure and function has tinuous Percoll gradient centrifugations that yielded an enriched Doccurred during eukaryotic evolution, and was especially mitosomal fraction suitable for proteome analysis [supporting observed in anaerobic/microaerophilic environments. Most extant information (SI) Fig. S1]. The presence of mitosomes was moni- anaerobic eukaryotes, which were previously considered to lack tored with the authentic mitosomal marker Cpn60. Mitosomes were mitochondria, are now regarded to possess reduced and highly recovered from fractions 19 and 20 in the first centrifugation and divergent forms of mitochondrion-related organelles (1, 2). The from fractions I through K in the second centrifugation with a peak hydrogenosome is an organelle in which hydrogen and ATP are in fraction J (Fig. 1). A list of mitosomal proteins was made by produced, and is found in anaerobic protists and fungi such as subtracting the proteins identified in fractions G and O from those Trichomonas vaginalis (3, 4), Neocallimastix patriciarum (5, 6), and in fraction J, as fraction J contained traces of either lysosome or ER protein, which were detected by markers cysteine protease 5 (CP5) Nyctotherus ovalis (7). The mitosome, typically demonstrated in ␣ parasitic and free-living protists such as E. histolytica (2, 8–15), and Sec61 , respectively (Fig. 1). Giardia intestinalis (16, 17), diverse microsporidian species (18–20), Survey of the Mitosomal Proteome. Three independent mitosomal and Cryptosporidium parvum (21), generally has reduced functions purifications and MS analysis reproducibly identified 95 putative and does not produce hydrogen or ATP. In Mastigamoeba bala- mitosomal proteins (Table S1). Although 64 of the proteins iden- muthi, a mitochondrion-related organelle was discovered and pre- tified were annotated in the E. histolytica genome database as sumed to possess a unique array of biochemical properties, although ‘‘hypothetical protein,’’ 3 enzymes involved in sulfate activation— it remains unclear whether the organelle is more similar to either ATP sulfurylase (AS) (25), APS kinase (APSK), and inorganic hydrogenosomes or mitosomes (22). In contrast, the mitochondri- pyrophosphatase (IPP)—were identified as dominant constituents, on-related organelle in Blastocystis contains DNA and shows char- based on the high coverage obtained for each protein (as described acteristics for both hydrogenosomes and mitochondria of higher eukaryotes (23). Organisms that possess hydrogenosomes and mitosomes do not cluster together in eukaryote phylogenies, indi- Author contributions: F.M. and T.N. designed research; F.M., M.A.Y., and K.N.-T. performed cating that secondary losses and changes in mitochondrial functions research; F.M. contributed new reagents/analytic tools; F.M. and T.N. analyzed data; and have independently occurred multiple times in eukaryote evolution F.M. and T.N. wrote the paper. (1). Although hydrogenosomes and mitosomes are divergent in The authors declare no conflict of interest. their contents and functions, a number of shared characteristics This article is a PNAS Direct Submission. A.R. is a guest editor invited by the Editorial Board. have been previously suggested, which include a double membrane, 1To whom correspondence should be addressed. E-mail: [email protected]. mitochondrial chaperonin 60 (Cpn60), and the iron sulfur cluster This article contains supporting information online at www.pnas.org/cgi/content/full/ (ISC) system (1). However, recent studies indicate that E. histolytica 0907106106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0907106106 PNAS Early Edition ͉ 1of6 Downloaded by guest on October 2, 2021 Fig. 1. Purification of mitosomes. Fractions derived from the first (fractions 1–20) and second (fractions A-S) discontinuous Percoll gradient centrifugation were electrophoresed on 5%–20% SDS/PAGE and sub- jected to immunoblot analyses using antibodies against well established organelle markers: Cpn60 (mi- tosome), cysteine synthase 1 (CS1; cytoplasm), Sec61␣ (endoplasmic reticulum), and CP5 (lysosome). later). Three transporters and 7 metabolic enzymes were also symporters identified in the E. histolytica genome (XP࿝649603, identified. In addition, 7 proteins involved in membrane trafficking, XP࿝654527, XP࿝654503, XP࿝655928, and XP࿝657578), colocalized including 4 Rab family GTPases, were detected. Furthermore, a with Cpn60, suggesting its involvement in the uptake and transport weak homologue of Tom40 (expectation value of 0.13), a compo- of sulfate into mitosomes (Fig. S2 E–H). nent of the transport complex of the outer membrane of the To further demonstrate the presence of a functional sulfate mitochondria, was identified. Three chaperones, Cpn60, Cpn10, activation pathway compartmentalized to mitosomes, AS and mitochondrial Hsp70, and MCF, which were previously reported as APSK activities were measured in the Percoll gradient centrifuga- tion fractions using Na [35S]O . Both [35S]-labeled adenosine-5Ј- Entamoeba mitosomal proteins (12–15), were also confirmed. Con- 2 4 phosphosulfate (APS) and 3Ј-phosphoadenosine-5Ј-phosphosul- versely, PNT and 2 proteins involved in the NIF system—NifS and fate (PAPS) were detected (Fig. 3). PAPS was predominantly NifU—were not detected. The proteome described here is likely to detected in fractions 19 and 20 of the first centrifugation and be partial, as only proteins enriched in fraction J were considered fractions I through K of the second centrifugation (Fig. 3). The as mitosomal proteins, although Cpn60 was detected throughout distribution of the PAPS-forming activity was similar to Cpn60 (Fig. fractions I through S in the second gradient (Fig. 1). The hetero- 1). In contrast, APS was detected in nearly all fractions (i.e., D-S) geneity displayed by mitosomes in the immunofluorescence assay of the second centrifugation. This suggests that AS is not exclusively (described later) also indicates that other subfractions of mitosomes localized to mitosomes,
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