Protein import and genome replication are essential processes for mitochondrial biogenesis and propagation. The J-domain proteins Pam16 and Pam18 regulate the presequence translocase of the mitochondrial inner membrane. In the protozoan Trypanosoma brucei, their counterparts are TbPam16 and TbPam18, which are essential for the procyclic form (PCF) of the parasite, though not involved in mitochondrial protein import. Here, we show that during evolution, the 2 proteins have been repurposed to regulate the replication of maxicircles within the intricate kDNA network, the most complex mitochondrial genome known. TbPam18 and TbPam16 have inactive J-domains suggesting a function independent of heat shock proteins. However, their single transmembrane domain is essential for function. Pulldown of TbPam16 identifies a putative client protein, termed MaRF11, the depletion of which causes the selective loss of maxicircles, akin to the effects observed for TbPam18 and TbPam16. Moreover, depletion of the mitochondrial proteasome results in increased levels of MaRF11. Thus, we have discovered a protein complex comprising TbPam18, TbPam16, and MaRF11, that controls maxicircle replication. We propose a working model in which the matrix protein MaRF11 functions downstream of the 2 integral inner membrane proteins TbPam18 and TbPam16. Moreover, we suggest that the levels of MaRF11 are controlled by the mitochondrial proteasome.

Department of Chemistry Biochemistry and Pharmaceutical Sciences University of Bern Bern Switzerland

Faculty of Chemistry and Pharmacy Biochemistry 2 Theodor Boveri Institute University of Würzburg Würzburg Germany

Faculty of Science University of South Bohemia České Budějovice Czech Republic

Institute of Parasitology Biology Centre České Budějovice Czech Republic

Zobrazit více v PubMed

Peikert CD, Mani J, Morgenstern M, Käser S, Knapp B, Wenger C, et al.. Charting organellar importomes by quantitative mass spectrometry. Nat Commun. 2017;8:15272. doi: 10.1038/ncomms15272 PubMed DOI PMC

Schneider A. Evolution and diversification of mitochondrial protein import systems. Curr Opin Cell Biol. 2022;75:102077. PubMed

Schneider A. Mitochondrial protein import in trypanosomatids: Variations on a theme or fundamentally different? PLoS Pathog. 2018;14:e1007351. PubMed PMC

Schneider A. Evolution of mitochondrial protein import—Lessons from trypanosomes. Biol Chem. 2020;401:663–676. doi: 10.1515/hsz-2019-0444 PubMed DOI

Harsman A, Schneider A. Mitochondrial protein import in trypanosomes: Expect the unexpected. Traffic. 2017;18:96–109. doi: 10.1111/tra.12463 PubMed DOI

Mani J, Meisinger C, Schneider A. Peeping at TOMs—Diverse entry gates to mitochondria provide insights into the evolution of eukaryotes. Mol Biol Evol. 2016;33:337–351. doi: 10.1093/molbev/msv219 PubMed DOI

Fukasawa Y, Oda T, Tomii K, Imai K. Origin and evolutionary alteration of the mitochondrial import system in eukaryotic lineages. Mol Biol Evol. 2017;34:1574. doi: 10.1093/molbev/msx096 PubMed DOI PMC

Žárský V, Doležal P. Evolution of the Tim17 protein family. Biol Direct. 2016;11. PubMed PMC

Ferramosca A, Zara V. Biogenesis of mitochondrial carrier proteins: Molecular mechanisms of import into mitochondria. Biochim Biophys Acta. 2013;1833:494–502. doi: 10.1016/j.bbamcr.2012.11.014 PubMed DOI

Zimmermann R, Neupert W. Transport of proteins into mitochondria: Posttranslational transfer of ADP/ATP carrier into mitochondria in vitro. Eur J Biochem. 1980;109:217–229. PubMed

Schulz C, Schendzielorz A, Rehling P. Unlocking the presequence import pathway. Trends Cell Biol. 2015;25:265–275. PubMed

Kang PJ, Ostermann J, Shilling J, Neupert W, Craig EA, Pfanner N, et al.. Requirement for Hsp70 in the mitochondrial matrix for translocation and folding of precursor proteins. Nature. 1990;348:137–143. doi: 10.1038/348137a0 PubMed DOI

Horst M, Oppliger W, Rospert S, Schönfeld HJ, Schatz G, Azem A. Sequential action of two Hsp70 complexes during protein import into mitochondria. EMBO J. 1997;16:1842. doi: 10.1093/emboj/16.8.1842 PubMed DOI PMC

D’Silva PD, Schilke B, Walter W, Andrew A, Craig EA. J protein cochaperone of the mitochondrial inner membrane required for protein import into the mitochondrial matrix. Proc Natl Acad Sci U S A. 2003;100:13839–13844. doi: 10.1073/pnas.1936150100 PubMed DOI PMC

Truscott KN, Voos W, Frazier AE, Lind M, Li Y, Geissler A, et al.. A J-protein is an essential subunit of the presequence translocase–associated protein import motor of mitochondria. J Cell Biol. 2003;163:707. PubMed PMC

Mokranjac D, Sichting M, Neupert W, Hell K. Tim14, a novel key component of the import motor of the TIM23 protein translocase of mitochondria. EMBO J. 2003;22:4945–4956. doi: 10.1093/emboj/cdg485 PubMed DOI PMC

Frazier AE, Dudek J, Guiard B, Voos W, Li Y, Lind M, et al.. Pam16 has an essential role in the mitochondrial protein import motor. Nat Struct Mol Biol. 2004;11:226–233. PubMed

Banerjee R, Gladkova C, Mapa K, Witte G, Mokranjac D. Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein. Elife. 2015;4. doi: 10.7554/eLife.11897 PubMed DOI PMC

Laloraya S, Gambill BD, Craig EA. A role for a eukaryotic GrpE-related protein, Mge1p, in protein translocation. Proc Natl Acad Sci U S A. 1994;91:6481–6485. doi: 10.1073/pnas.91.14.6481 PubMed DOI PMC

Laloraya S, Dekker PJT, Voos W, Craig EA, Pfanner N. Mitochondrial GrpE modulates the function of matrix Hsp70 in translocation and maturation of preproteins. Mol Cell Biol. 1995;15:7098–7105. doi: 10.1128/MCB.15.12.7098 PubMed DOI PMC

Schneider HC, Westermann B, Neupert W, Brunner M. The nucleotide exchange factor MGE exerts a key function in the ATP-dependent cycle of mt-Hsp70-Tim44 interaction driving mitochondrial protein import. EMBO J. 1996;15:5796–5803. PubMed PMC

Harsman A., Oeljeklaus S., Wenger C, Huot JH, Warscheid B Schneider A. The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins. Nat Commun 2016;7:1–13. doi: 10.1038/ncomms13707 PubMed DOI PMC

Pyrihová E, Motyková A, Voleman L, Wandyszewska N, Fišer R, Seydlová G, et al.. A single TIM translocase in the mitosomes of Giardia intestinalis illustrates convergence of protein import machines in anaerobic eukaryotes. Genome Biol Evol. 2018;10:2813–2822. doi: 10.1093/gbe/evy215 PubMed DOI PMC

Singha UK, Hamilton V, Duncan MR, Weems E, Tripathi MK, Chaudhuri M. Protein translocase of mitochondrial inner membrane in Trypanosoma brucei. J Biol Chem. 2012;287:14480. PubMed PMC

Tschopp F, Charrière F, Schneider A. In vivo study in Trypanosoma brucei links mitochondrial transfer RNA import to mitochondrial protein import. EMBO Rep. 2011;12:825–832. PubMed PMC

von Känel C, Muñoz-Gómez SA, Oeljeklaus S, Wenger C, Warscheid B, Wideman JG, et al.. Homologue replacement in the import motor of the mitochondrial inner membrane of trypanosomes. Elife. 2020;9. doi: 10.7554/eLife.52560 PubMed DOI PMC

Verner Z, Basu S, Benz C, Dixit S, Dobáková E, Faktorová D, et al.. Malleable mitochondrion of Trypanosoma brucei. Int Rev Cell Mol Biol. 2015;315:73–151. doi: 10.1016/bs.ircmb.2014.11.001 PubMed DOI

Jensen RE, Englund PT. Network News: The replication of kinetoplast DNA. Annu Rev Microbiol. 2012;66:473–491. doi: 10.1146/annurev-micro-092611-150057 PubMed DOI

Ramrath DJF, Niemann M, Leibundgut M, Bieri P, Prange C, Horn EK, et al.. Evolutionary shift toward protein-based architecture in trypanosomal mitochondrial ribosomes. Science. 2018;362(6413):eaau7735 doi: 10.1126/science.aau7735 PubMed DOI

Schneider A. A short history of guide RNAs. EMBO Rep. 2020;21:e51918. PubMed PMC

Read LK, Lukeš J, Hashimi H. Trypanosome RNA editing: The complexity of getting U in and taking U out. Wiley Interdiscip Rev RNA. 2016;7:33–51. doi: 10.1002/wrna.1313 PubMed DOI PMC

Stuart KD, Schnaufer A, Ernst NL, Panigrahi AK. Complex management: RNA editing in trypanosomes. Trends Biochem Sci. 2005;30:97–105. PubMed

Hajduk S, Ochsenreiter T. RNA editing in kinetoplastids. RNA Biol. 2010;7:229–236. doi: 10.4161/rna.7.2.11393 PubMed DOI

Cooper S, Wadsworth ES, Ochsenreiter T, Ivens A, Savill NJ, Schnaufer A. Assembly and annotation of the mitochondrial minicircle genome of a differentiation-competent strain of Trypanosoma brucei. Nucleic Acids Res. 2019;47:11304–11325. doi: 10.1093/nar/gkz928 PubMed DOI PMC

Shapiro TA. Kinetoplast DNA maxicircles: networks within networks. PNAS. 1993;90:7809–7813. doi: 10.1073/pnas.90.16.7809 PubMed DOI PMC

Chen J, Rauch CA, White JH, Englund PT, Cozzarelli NR. The topology of the kinetoplast DNA network. Cell. 1995;80:61–69. PubMed

Schneider A, Ochsenreiter T. Failure is not an option—mitochondrial genome segregation in trypanosomes. J Cell Sci. 2018;131. PubMed

Ogbadoyi EO, Robinson DR, Gull K. A high-order trans-membrane structural linkage is responsible for mitochondrial genome positioning and segregation by flagellar basal bodies in trypanosomes. Mol Biol Cell. 2003;14:1769–1779. doi: 10.1091/mbc.e02-08-0525 PubMed DOI PMC

Drew ME, Englund PT. Intramitochondrial location and dynamics of Crithidia fasciculata kinetoplast minicircle replication intermediates. J Cell Biol. 2001;153:735–744. PubMed PMC

Ryant KA, Englund PT. Synthesis and processing of kinetoplast DNA minicircles in Trypanosoma equiperdum. Mol Cell Biol. 1989;9:3212. doi: 10.1128/mcb.9.8.3212-3217.1989 PubMed DOI PMC

Melendy T, Sheline C, Ray DS. Localization of a type II DNA topoisomerase to two sites at the periphery of the kinetoplast DNA of Crithidia fasciculata. Cell. 1988;55:1083–1088. doi: 10.1016/0092-8674(88)90252-8 PubMed DOI

Ryan KA, Englund PT. Replication of kinetoplast DNA in Trypanosoma equiperdum: Minicircle H strand fragments which map at specific locations. J Biol Chem. 1989;264:823–830. PubMed

Amodeo S, Bregy I, Ochsenreiter T. Mitochondrial genome maintenance—the kinetoplast story. FEMS Microbiol Rev. 2022. doi: 10.1093/FEMSRE/FUAC047 PubMed DOI PMC

Povelones ML. Beyond replication: Division and segregation of mitochondrial DNA in kinetoplastids. Mol Biochem Parasitol. 2014;196:53–60. doi: 10.1016/j.molbiopara.2014.03.008 PubMed DOI

Gluenz E, Povelones ML, Englund PT, Gull K. The kinetoplast duplication cycle in Trypanosoma brucei is orchestrated by cytoskeleton-mediated cell morphogenesis. Mol Cell Biol. 2011;31:1012–1021. doi: 10.1128/MCB.01176-10 PubMed DOI PMC

Li Z, Lindsay ME, Motyka SA, Englund PT, Wang CC. Identification of a bacterial-like HslVU protease in the mitochondria of Trypanosoma brucei and its role in mitochondrial DNA replication. PLoS Pathog. 2008;4. PubMed PMC

Liu B, Wang J, Yaffe N, Lindsay M, Zhao Z, Zick A, et al.. Trypanosomes have six mitochondrial DNA helicases with one controlling kinetoplast maxicircle replication. Mol Cell. 2009;35:490–501. doi: 10.1016/j.molcel.2009.07.004 PubMed DOI PMC

Zíková A, Verner Z, Nenarokova A, Michels PAM, Lukeš J. A paradigm shift: The mitoproteomes of procyclic and bloodstream Trypanosoma brucei are comparably complex. PLoS Pathog. 2017;13:e1006679. doi: 10.1371/journal.ppat.1006679 PubMed DOI PMC

Clement SL, Mingler MK, Koslowsky DJ. An Intragenic Guide RNA Location Suggests a Complex Mechanism for Mitochondrial Gene Expression in Trypanosoma brucei. Eukaryot Cell. 2004;3:862. PubMed PMC

Harsman A, Oeljeklaus WC, Huot JL, Warscheid B, Schneider A. The non-canonical mitochondrial inner membrane presequence translocase of trypanosomatids contains two essential rhomboid-like proteins. Nat Commun. 2016;7:1–13. PubMed PMC

Amodeo S, Jakob M, Ochsenreiter T. Characterization of the novel mitochondrial genome replication factor MiRF172 in Trypanosoma brucei. J Cell Sci. 2018;131. doi: 10.1242/jcs.211730 PubMed DOI PMC

Hines JC, Ray DS. A mitochondrial DNA primase is essential for cell growth and kinetoplast DNA replication in Trypanosoma brucei. Mol Cell Biol. 2010;30:1319–1328. doi: 10.1128/MCB.01231-09 PubMed DOI PMC

Týč J, Klingbeil MM, Lukeš J. Mitochondrial heat shock protein machinery hsp70/hsp40 is indispensable for proper mitochondrial DNA maintenance and replication. MBio. 2015;6. doi: 10.1128/mBio.02425-14 PubMed DOI PMC

Beck K, Acestor N, Schulfer A, Anupama A, Carnes J, Panigrahi AK, et al.. Trypanosoma brucei Tb927.2.6100 is an essential protein associated with kinetoplast DNA. Eukaryot Cell. 2013;12:970–978. PubMed PMC

Grewal JS, McLuskey K, Das D, Myburgh E, Wilkes J, Brown E, et al.. PNT1 is a C11 cysteine peptidase essential for replication of the trypanosome kinetoplast. J Biol Chem. 2016;291:9492–9500. doi: 10.1074/jbc.M116.714972 PubMed DOI PMC

Singha UK, Tripathi A, Smith JJ, Quinones L, Saha A, Singha T, et al.. Novel IM-associated protein Tim54 plays a role in the mitochondrial import of internal signal-containing proteins in Trypanosoma brucei. Biol Cell. 2021;113:39–57. doi: 10.1111/boc.202000054 PubMed DOI PMC

von Känel C, Oeljeklaus S, Wenger C, Stettler P, Harsman A, Warscheid B, et al.. Intermembrane space-localized TbTim15 is an essential subunit of the single mitochondrial inner membrane protein translocase of trypanosomes. Mol Microbiol. 2024. doi: 10.1111/mmi.15262 PubMed DOI

Bhat GJ, Koslowsky DJ, Feagin JE, Smiley BL, Stuart K. An extensively edited mitochondrial transcript in kinetoplastids encodes a protein homologous to ATPase subunit 6. Cell. 1990;61:885–894. doi: 10.1016/0092-8674(90)90199-o PubMed DOI

Dean S, Gould MK, Dewar CE, Schnaufer AC. Single point mutations in ATP synthase compensate for mitochondrial genome loss in trypanosomes. Proc Natl Acad Sci U S A. 2013;110:14741–14746. PubMed PMC

Wirtz E, Lea S, Ochatt C, Cross GAM. A tightly regulated inducible expression system for conditional gene knock-outs and dominant-negative genetics in Trypanosoma brucei. Mol Biochem Parasitol. 1999;99:89–101. doi: 10.1016/s0166-6851(99)00002-x PubMed DOI

Krogh A, Larsson B, von Heijne G, Sonnhammer ELL. Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J Mol Biol. 2001;305:567–580. doi: 10.1006/jmbi.2000.4315 PubMed DOI

Kampinga HH, Andreasson C, Barducci A, Cheetham ME, Cyr D, Emanuelsson C, et al.. Function, evolution, and structure of J-domain proteins. Cell Stress Chaperones. 2018;24:7–15. PubMed PMC

Walsh P, Bursać D, Law YC, Cyr D, Lithgow T. The J-protein family: modulating protein assembly, disassembly and translocation. EMBO Rep. 2004;5:567–571. PubMed PMC

Oeljeklaus S, Reinartz BS, Wolf J, Wiese S, Tonillo J, Podwojski K, et al.. Identification of core components and transient interactors of the peroxisomal importomer by dual-track stable isotope labeling with amino acids in cell culture analysis. J Proteome Res. 2012;11:2567–2580. PubMed

Wheeler RJ. A resource for improved predictions of Trypanosoma and Leishmania protein three-dimensional structure. PLoS ONE. 2021;16:e0259871. doi: 10.1371/journal.pone.0259871 PubMed DOI PMC

Stefely JA, Pagliarini DJ. Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. Trends Biochem Sci. 2017;42:824–843. PubMed PMC

Priesnitz C, Böttinger L, Zufall N, Gebert M, Guiard B, van der Laan M, et al.. Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation. Cell Rep. 2022;39:110619. doi: 10.1016/j.celrep.2022.110619 PubMed DOI

Grams J, Morris JC, Drew ME, Wang Z, Englund PT, Hajduk SL, et al.. A trypanosome mitochondrial RNA polymerase is required for transcription and replication. J Biol Chem. 2002;277:16952–16959. doi: 10.1074/jbc.M200662200 PubMed DOI

Hammarton TC, Clark J, Douglas F, Boshart M, Mottram JC. Stage-specific differences in cell cycle control in Trypanosoma brucei revealed by RNA interference of a mitotic cyclin. J Biol Chem. 2003;278:22877–22886. doi: 10.1074/jbc.M300813200 PubMed DOI

Mokranjac D, Bourenkov G, Hell K, Neupert W, Groll M. Structure and function of Tim14 and Tim16, the J and J-like components of the mitochondrial protein import motor. EMBO J. 2006;25:4675–4685. doi: 10.1038/sj.emboj.7601334 PubMed DOI PMC

Rocco L, Englund PT. Kinetoplast maxicircle DNA replication in Crithidia fasciculata and Trypanosoma brucei. Mol Cell Biol. 1995;15:6794–6803. doi: 10.1128/MCB.15.12.6794 PubMed DOI PMC

Hoffmann A, Käser S, Jakob M, Amodeo S, Peitsch C, Týč J, et al.. Molecular model of the mitochondrial genome segregation machinery in Trypanosoma brucei. Proc Natl Acad Sci U S A. 2018;115:E1809–E1818. doi: 10.1073/pnas.1716582115 PubMed DOI PMC

Schimanski B, Aeschlimann S, Stettler P, Käser S, Gomez-Fabra GM, Bender J, et al.. p166 links membrane and intramitochondrial modules of the trypanosomal tripartite attachment complex. PLoS Pathog. 2022;18:e1010207. doi: 10.1371/journal.ppat.1010207 PubMed DOI PMC

Aeschlimann S, Stettler P, Schneider A. DNA segregation in mitochondria and beyond: insights from the trypanosomal tripartite attachment complex. Trends Biochem Sci. 2023. doi: 10.1016/J.TIBS.2023.08.012 PubMed DOI

Craig EA, Marszalek J. How do J-proteins get Hsp70 to do so many different things? Trends Biochem Sci. 2017;42:355–368. doi: 10.1016/j.tibs.2017.02.007 PubMed DOI PMC

Craig EA, Huang P, Aron R, Andrew A. The diverse roles of J-proteins, the obligate Hsp70 co-chaperone. Rev Physiol Biochem Pharmacol. 2006;156:1–21. doi: 10.1007/s10254-005-0001-0 PubMed DOI

Bentley SJ, Jamabo M, Boshoff A. The Hsp70/J-protein machinery of the African trypanosome, Trypanosoma brucei. Cell Stress Chaperones. 2018;24:125–148. doi: 10.1007/s12192-018-0950-x PubMed DOI PMC

Panigrahi AK, Ogata Y, Zíková A, Anupama A, Dalley RA, Acestor N, et al.. A comprehensive analysis of Trypanosoma brucei mitochondrial proteome. Proteomics. 2009;9:434–450. doi: 10.1002/pmic.200800477 PubMed DOI PMC

Acestor N, Zíková A, Dalley RA, Anupama A, Panigrahi AK, Stuart KD. Trypanosoma brucei mitochondrial respiratome: Composition and organization in procyclic form. Mol Cell Proteomics. 2011;10. PubMed PMC

Acestor N, Panigrahi AK, Ogata Y, Anupama A, Stuart KD. Protein composition of Trypanosoma brucei mitochondrial membranes. Proteomics. 2009;9:5497–5508. doi: 10.1002/pmic.200900354 PubMed DOI PMC

Niemann M, Wiese S, Mani J, Chanfon A, Jackson C, Meisinger C, et al.. Mitochondrial outer membrane proteome of Trypanosoma brucei reveals novel factors required to maintain mitochondrial morphology. Mol Cell Proteomics. 2013;12:515–528. doi: 10.1074/mcp.M112.023093 PubMed DOI PMC

Kityk R, Kopp J, Mayer MP. Molecular mechanism of J-domain-triggered ATP hydrolysis by Hsp70 chaperones. Mol Cell. 2018;69:227–237.e4. doi: 10.1016/j.molcel.2017.12.003 PubMed DOI

Pulido P, Leister D. Novel DNAJ-related proteins in Arabidopsis thaliana. New Phytol. 2018;217:480–490. doi: 10.1111/nph.14827 PubMed DOI

Tamadaddi C, Verma AK, Zambare V, Vairagkar A, Diwan D, Sahi C. J-like protein family of Arabidopsis thaliana: the enigmatic cousins of J-domain proteins. Plant Cell Rep. 2022;1:1–13. doi: 10.1007/s00299-022-02857-y PubMed DOI

Woodward R, Gull K. Timing of nuclear and kinetoplast DNA replication and early morphological events in the cell cycle of Trypanosoma brucei. J Cell Sci. 1990;95(Pt 1):49–57. PubMed

Moloney NM, Barylyuk K, Tromer E, Crook OM, Breckels LM, Lilley KS, et al.. Mapping diversity in African trypanosomes using high resolution spatial proteomics. Nat Commun. 2023;14. PubMed PMC

Schönenberger M, Brun R. Cultivation and in vitro cloning of procyclic culture forms of ‘Trypanosoma brucei’ in a semi-defined medium: short communication. ActaTropica. 1979;36:289–292. PubMed

Hirumi H, Hirumi K. Continuous cultivation of Trypanosoma brucei blood stream forms in a medium containing a low concentration of serum protein without feeder cell layers. J Parasitol. 1989;75:985–989. PubMed

Bochud-Allemann N, Schneider A. Mitochondrial Substrate Level Phosphorylation Is Essential for Growth of Procyclic Trypanosoma brucei. J Biol Chem. 2002;277:32849–32854. PubMed

Oberholzer M, Morand S, Kunz S, Seebeck T. A vector series for rapid PCR-mediated C-terminal in situ tagging of Trypanosoma brucei genes. Mol Biochem Parasitol. 2006;145:117–120. doi: 10.1016/j.molbiopara.2005.09.002 PubMed DOI

Mani J, Desy S, Niemann M, Chanfon A, Oeljeklaus S, Pusnik M, et al.. Mitochondrial protein import receptors in Kinetoplastids reveal convergent evolution over large phylogenetic distances. Nat Commun. 2015;6:1–12. doi: 10.1038/ncomms7646 PubMed DOI PMC

Abràmoff MD, Magalhaes PJ, Ram SJ. Image Processing with ImageJ. Biophotonics Int. 2004;11:36–42.

Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159. doi: 10.1006/abio.1987.9999 PubMed DOI

Trikin R, Doiron N, Hoffmann A, Haenni B, Jakob M, Schnaufer A, et al.. TAC102 Is a Novel Component of the Mitochondrial Genome Segregation Machinery in Trypanosomes. PLoS Pathog. 2016;12:e1005586. PubMed PMC

Liu B, Molina H, Kalume D, Pandey A, Griffith JD, Englund PT. Role of p38 in replication of Trypanosoma brucei kinetoplast DNA. Mol Cell Biol. 2006;26:5382–5393. doi: 10.1128/MCB.00369-06 PubMed DOI PMC

Lamour N, Rivière L, Coustou V, Coombs GH, Barrett MP, Bringaud F. Proline metabolism in procyclic Trypanosoma brucei is down-regulated in the presence of glucose. J Biol Chem. 2005;280:11902–11910. doi: 10.1074/jbc.M414274200 PubMed DOI

Eichenberger C, Oeljeklaus S, Bruggisser J, Mani J, Haenni B, Kaurov I, et al.. The highly diverged trypanosomal MICOS complex is organized in a nonessential integral membrane and an essential peripheral module. Mol Microbiol. 2019;112:1731–1743. doi: 10.1111/mmi.14389 PubMed DOI

Wenger C, Harsman A, Niemann M, Oeljeklaus S, von Känel C, Calderaro S, et al.. The Mba1 homologue of Trypanosoma brucei is involved in the biogenesis of oxidative phosphorylation complexes. Mol Microbiol. 2023;119:537–550. doi: 10.1111/mmi.15048 PubMed DOI

Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–1372. doi: 10.1038/nbt.1511 PubMed DOI

Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: A peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–1805. doi: 10.1021/pr101065j PubMed DOI

Cleveland WS, Devlin SJ. Locally Weighted Regression: An Approach to Regression Analysis by Local Fitting. J Am Stat Assoc. 1988;83:596–610.

Gautier L, Cope L, Bolstad BM, Irizarry RA. Affy—Analysis of Affymetrix GeneChip data at the probe level. Bioinformatics. 2004;20:307–315. doi: 10.1093/bioinformatics/btg405 PubMed DOI

Egert J, Brombacher E, Warscheid B, Kreutz C. DIMA: Data-Driven Selection of an Imputation Algorithm. J Proteome Res. 2021;20:3489–3496. PubMed

Schwämmle V, León IR, Jensen ON. Assessment and improvement of statistical tools for comparative proteomics analysis of sparse data sets with few experimental replicates. J Proteome Res. 2013;12:3874–3883. doi: 10.1021/pr400045u PubMed DOI

Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3. PubMed

Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc B Methodol. 1995;57:289–300.

Breitling R, Herzyk P. Rank-based methods as a non-parametric alternative of the T-statistic for the analysis of biological microarray data. J Bioinform Comput Biol. 2005;3:1171–1189. doi: 10.1142/s0219720005001442 PubMed DOI

Dewar CE, Oeljeklaus S, Mani J, Mühlhäuser WWD, von Känel C, Zimmermann J, et al.. Mistargeting of aggregation prone mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes. Nat Commun. 2022;13. PubMed PMC

Del Carratore F, Jankevics A, Eisinga R, Heskes T, Hong F, Breitling R. RankProd 2.0: a refactored bioconductor package for detecting differentially expressed features in molecular profiling datasets. Bioinformatics. 2017;33:2774. PubMed PMC