The Mitochondrial Prohibitin Complex Is Essential for Embryonic Viability and Germline Function in Caenorhabditis elegans

Prohibitins in eukaryotes consist of two subunits (PHB1 and PHB2) that together form a high molecular weight complex in the mitochondrial inner membrane. The evolutionary conservation and the ubiquitous expression in mammalian tissues of the prohibitin complex suggest an important function among eukaryotes. The PHB complex has been shown to play a role in the stabilization of newly synthesized subunits of mitochondrial respiratory enzymes in the yeast Saccharomyces cerevisiae. We have used Caenorhabditis elegans as model system to study the role of the PHB complex during development of a multicellular organism. We demonstrate that prohibitins in C. elegans form a high molecular weight complex in the mitochondrial inner membrane similar to that of yeast and humans. By using RNA-mediated gene inactivation, we show that PHB proteins are essential during embryonic development and are required for somatic and germline differentiation in the larval gonad. We further demonstrate that a deficiency in PHB proteins results in altered mitochondrial biogenesis in body wall muscle cells. This paper reports a strong loss of function phenotype for prohibitin gene inactivation in a multicellular organism and shows for the first time that prohibitins serve an essential role in mitochondrial function during organismal development. Prohibitins in eukaryotes consist of two subunits (PHB1 and PHB2) that together form a high molecular weight complex in the mitochondrial inner membrane. The evolutionary conservation and the ubiquitous expression in mammalian tissues of the prohibitin complex suggest an important function among eukaryotes. The PHB complex has been shown to play a role in the stabilization of newly synthesized subunits of mitochondrial respiratory enzymes in the yeast Saccharomyces cerevisiae. We have used Caenorhabditis elegans as model system to study the role of the PHB complex during development of a multicellular organism. We demonstrate that prohibitins in C. elegans form a high molecular weight complex in the mitochondrial inner membrane similar to that of yeast and humans. By using RNA-mediated gene inactivation, we show that PHB proteins are essential during embryonic development and are required for somatic and germline differentiation in the larval gonad. We further demonstrate that a deficiency in PHB proteins results in altered mitochondrial biogenesis in body wall muscle cells. This paper reports a strong loss of function phenotype for prohibitin gene inactivation in a multicellular organism and shows for the first time that prohibitins serve an essential role in mitochondrial function during organismal development. Prohibitins (Phb1p and Phb2p), referred to here as PHB proteins, are evolutionarily strongly conserved proteins that are located in mitochondria in yeast, plants, and mammals (1Ikonen E. Fiedler K. Parton R.G. Simons K. FEBS Lett. 1995; 358: 273-277Crossref PubMed Scopus (168) Google Scholar, 2Snedden W.A. Plant Mol. Biol. 1997; 33: 753-756Crossref PubMed Scopus (59) Google Scholar, 3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar, 4Berger K.H. Yaffe M.P. Mol. Cell. Biol. 1998; 18: 4043-4052Crossref PubMed Scopus (160) Google Scholar, 5Steglich G. Neupert W. Langer T. Mol. Cell. Biol. 1999; 19: 3435-3442Crossref PubMed Google Scholar, 6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). In mammalian and yeast cells, it has been demonstrated that PHB proteins associate with each other to form a high molecular weight complex (the PHB complex) in the mitochondrial inner membrane (5Steglich G. Neupert W. Langer T. Mol. Cell. Biol. 1999; 19: 3435-3442Crossref PubMed Google Scholar, 6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). Although diverse cellular functions have been attributed to both PHB proteins (see Ref. 7Nijtmans L.G. Artal S.M. Grivell L.A. Coates P.J. Cell Mol. Life Sci. 2002; 59: 143-155Crossref PubMed Scopus (250) Google Scholar for a review), such as a role in cell cycle regulation (8McClung J.K. Danner D.B. Stewart D.A. Smith J.R. Schneider E.L. Lumpkin C.K. Dell'Orco R.T. Nuell M.J. Biochem. Biophys. Res. Commun. 1989; 164: 1316-1322Crossref PubMed Scopus (144) Google Scholar, 9Nuell M.J. Stewart D.A. Walker L. Friedman V. Wood C.M. Owens G.A. Smith J.R. Schneider E.L. Dell' Orco R. Lumpkin C.K. Danner D.B. McClung J.K. Mol. Cell. Biol. 1991; 11: 1372-1381Crossref PubMed Scopus (228) Google Scholar, 10Wang S. Nath N. Adlam M. Chellappan S. Oncogene. 1999; 18: 3501-3510Crossref PubMed Scopus (204) Google Scholar, 11Wang S. Nath N. Fusaro G. Chellappan S. Mol. Cell. Biol. 1999; 19: 7447-7460Crossref PubMed Scopus (142) Google Scholar) and in cell surface signaling (12Terashima M. Kim K.-M. Takahiro Adachi e. Lamers M.C. EMBO J. 1994; 13: 3782-3792Crossref PubMed Scopus (206) Google Scholar, 13Montano M.M. Ekena K. Delage-Mourroux R. Chang W. Martini P. Katzenellenbogen B.S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 6947-6952Crossref PubMed Scopus (242) Google Scholar), these functions are difficult to reconcile with the exclusive localization of mammalian PHB proteins to mitochondria (1Ikonen E. Fiedler K. Parton R.G. Simons K. FEBS Lett. 1995; 358: 273-277Crossref PubMed Scopus (168) Google Scholar, 3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). To date, studies on the yeast PHB complex have provided convincing evidence for a direct role in mitochondrial function. The PHB complex has been found to co-purify with the m-AAA (matrix-ATPase associated with a variety of cellular activities) protease, and a role as a negative regulator of the protease has been proposed (5Steglich G. Neupert W. Langer T. Mol. Cell. Biol. 1999; 19: 3435-3442Crossref PubMed Google Scholar). Yeast PHB proteins are capable of stabilizing newly synthesized mitochondrially encoded proteins through direct interaction, suggesting a role in mitochondrial respiratory complex assembly (5Steglich G. Neupert W. Langer T. Mol. Cell. Biol. 1999; 19: 3435-3442Crossref PubMed Google Scholar, 6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). We have suggested a role for PHB proteins in the biogenesis of mitochondria as a holdase/unfoldase type of protein specifically required in situations of metabolic stress (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). Based on structural data from chemical cross-linking and mass spectrometry, we predict a barrel-like structure for the yeast PHB complex, in the cavity of which mitochondrial products might be held (14Back J.W. Sanz M.A. De Jong L. De Koning L.J. Nijtmans L.G. De Koster C.G. Grivell L.A. Van Der Spek H. Muijsers A.O. Protein Sci. 2002; 11: 2471-2478Crossref PubMed Scopus (142) Google Scholar). At the phenotypic level, disruption of PHB genes in yeast results in a shortening of the replicative life span due to premature aging (3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). This shortening of life span contrasts with the lack of an observable growth phenotype under laboratory conditions. However, deletion of PHB genes is lethal in combination with mutations of the mitochondrial inheritance machinery (4Berger K.H. Yaffe M.P. Mol. Cell. Biol. 1998; 18: 4043-4052Crossref PubMed Scopus (160) Google Scholar), of the AAA-mitochondrial proteases (5Steglich G. Neupert W. Langer T. Mol. Cell. Biol. 1999; 19: 3435-3442Crossref PubMed Google Scholar), or of the mitochondrial phosphatidylethanolamine biosynthetic machinery (15Birner R. Nebauer R. Schneiter R. Daum G. Mol. Biol. Cell. 2003; 14: 370-383Crossref PubMed Scopus (79) Google Scholar). The lack of a clear growth phenotype in yeast PHB mutants might reflect a redundancy in assembly factors. Alternatively, PHB mutations may have a stronger phenotype in organisms or tissues with a greater dependence on mitochondrial energy generation. In support of this latter hypothesis, deletion of a PHB homologue in Drosophila melanogaster results in lethality during larval development (16Eveleth Jr., D.D. Marsh J.L. Nucleic Acids Res. 1986; 14: 6169-6183Crossref PubMed Scopus (70) Google Scholar), suggesting that PHB proteins are essential during one or more steps in the differentiation of multicellular organisms. In this study, we have used Caenorhabditis elegans as a model organism to study the role of PHB proteins during organismal development. First, we demonstrate by blue native electrophoresis (BNE) 1The abbreviations used are: BNE, blue native electrophoresis; RNAi, RNA-mediated interference; mitochondrial respiratory abbreviations used are: BNE, blue native electrophoresis; RNAi, RNA-mediated interference; mitochondrial respiratory that PHB proteins in the form a high molecular weight complex in the mitochondrial membrane similar to that in yeast and (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). by using RNA-mediated we the of PHB proteins of PHB proteins during results in PHB are during somatic and germline are from to with a high of embryonic lethality of the a body and a somatic gonad. direct to mitochondrial is demonstrated by the altered mitochondrial in body wall muscle of We a in with In we show that PHB protein are in situations of altered mitochondrial such as in respiratory subunits as has been in other (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar, L.G. Artal Sanz M. M. M. G.A. M. Grivell L.A. FEBS Lett. PubMed Scopus (59) Google Scholar, P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). 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K. 1998; PubMed Scopus Google Scholar) with by for and with and with M.M. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The in a and with a The for The for and the in as H. G. Biochem. 1991; PubMed Scopus Google Scholar) using in of for and the proteins on H. G. Biochem. PubMed Scopus Google Scholar). proteins to and by to the and on growth with or or and or for and in first of To to using of as K. De A. J.R. 2002; PubMed Scopus Google Scholar) using a with or and in of of the in of The and for on the The of the of the used to the and for protein to protein We with an of by a in which have or J. and J. R. the D.A. van der Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and the by to for the of the protein has been (3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). the yeast of a from from and used a of on and under a with a or a with a C. elegans a PHB in the C. elegans data two and with the yeast and genes C. elegans 1998; PubMed Scopus Google Scholar). with the and yeast PHB proteins and as of and (see and for of and C. elegans PHB proteins is shown in We to and in to the proposed L.G. Artal S.M. Grivell L.A. Coates P.J. Cell Mol. Life Sci. 2002; 59: 143-155Crossref PubMed Scopus (250) Google Scholar). the proteins, we the and gene and protein be by the and for the C. elegans gene and has been shown that together the PHB proteins form a high molecular weight complex with an of in the mitochondrial inner membrane of yeast and (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). To the of the C. elegans PHB complex, mitochondrial membrane by electrophoresis H. G. Biochem. 1991; PubMed Scopus Google Scholar). In the first membrane protein are by blue native electrophoresis to In the protein subunits of this with the the of the protein (3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). in the with of and in the the of The for and are and the these and the of the protein complex in the first is similar to the of the yeast and PHB (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar), we the and to and evidence is This that in C. elegans the PHB proteins form a mitochondrial complex similar to PHB of other (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). The A. G. E.L. J. Mol. Biol. PubMed Scopus Google Scholar) a for is for This is in with for the yeast PHB proteins (14Back J.W. Sanz M.A. De Jong L. De Koning L.J. Nijtmans L.G. De Koster C.G. Grivell L.A. Van Der Spek H. Muijsers A.O. Protein Sci. 2002; 11: 2471-2478Crossref PubMed Scopus (142) Google Scholar). The yeast PHB proteins are mitochondria the of an (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). that the protein on with the molecular weight of the proteins and the with yeast it is to that the C. elegans PHB proteins are to mitochondria of a and that the of is in the protein as in the PHB during is the in which of results in and inactivation of the gene through the of A. 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We by E. to and to the of both and with or The to and the on the for or in embryonic of with lethality under and conditions. embryonic with or in the of The development of by in with from the to the This may reflect in the of in each PHB for the of gene essential for embryonic development. a in development. and of and and of and and of with a high of in the The for or under the and somatic a body and are the of and and and and and that are for the or of in the be and of the the and of the by and from on for and The results show that is in the for or for a gene the mitochondrial with To the and of the during larval and to The and The results show that is for and for are type To the of on PHB protein mitochondria from or from the membrane proteins from from and from by shows a clear in the of the two PHB proteins in both results are in with in yeast, the disruption of gene to the loss of both proteins, the for the gene be (4Berger K.H. Yaffe M.P. Mol. Cell. Biol. 1998; 18: 4043-4052Crossref PubMed Scopus (160) Google Scholar). in yeast (4Berger K.H. Yaffe M.P. Mol. Cell. Biol. 1998; 18: 4043-4052Crossref PubMed Scopus (160) Google Scholar, 6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar), the C. elegans and subunits are for assembly and protein results that for both and genes is and Although the and genes are to further the and of the and of or the cycle is in of more and and with the and data the of with type have and for for in a The body and and are with To further this we the of growth which may metabolic due to metabolic W.A. S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). The of with from to to for and from to to for a with and in the of of PHB proteins on mitochondrial we of (see and for shown in the are with and for and in are associated with and J. G. 2003; 33: PubMed Scopus Google Scholar). The C. elegans and it for the of We used a a mitochondrially protein from the D.A. van der Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). wall muscle mitochondria in and to the body and to the D.A. van der Mol. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In in muscle mitochondria and and to PHB complex has been suggested to play a role in the assembly of (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). in the mitochondrial respiratory to the of and to We and in the of of which the of are more to This that a deficiency in PHB proteins may in an in the of the to with an in a to or in of PHB protein expression is an in the of mitochondrial respiratory subunits in yeast (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar, L.G. Artal Sanz M. M. M. G.A. M. Grivell L.A. FEBS Lett. PubMed Scopus (59) Google Scholar) and in P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). To this in C. with a of mitochondrial C. P. C. A. Cell Res. PubMed Scopus Google Scholar), and to to the and PHB protein by development to or the D.B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). In the in PHB protein and of with We have that the yeast PHB complex newly synthesized mitochondrial products by with and have suggested a role in the assembly of mitochondrial respiratory (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar). disruption in yeast results in a in replicative life due to a in cellular metabolic (3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). In disruption of the Drosophila homologue of prohibitin is lethal during from to (16Eveleth Jr., D.D. Marsh J.L. Nucleic Acids Res. 1986; 14: 6169-6183Crossref PubMed Scopus (70) Google Scholar), suggesting a strong dependence of these on prohibitin function. To further we to study the of lack of prohibitins during the development of Caenorhabditis C. elegans two genes that we have and of shows that both genes are and We demonstrate by blue native electrophoresis that the gene products form a complex in the mitochondrial inner membrane as in other organisms the that the PHB complex is in or as by that in C. elegans and are the of protein complex as we and have in yeast (4Berger K.H. Yaffe M.P. Mol. Cell. Biol. 1998; 18: 4043-4052Crossref PubMed Scopus (160) Google Scholar, 6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar) and P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). The used in this study the of the protein (3Coates P.J. Curr. Biol. 1997; 7: 607-610Abstract Full Text Full Text PDF PubMed Google Scholar). The two of and in C. to the protein of the The with the We that to the and proteins for the the are in mitochondrial membrane and as a high molecular weight complex in the first of as in other the of the two and both are a that has been shown to of PHB proteins in mammals P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar) and is similar to situations in yeast (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. 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The in C. elegans strongly that prohibitins are specifically required during cellular and germline are and the germline is the during it may metabolic and be more to the loss of function of PHB proteins other somatic This is in with in mammalian cells. is that prohibitins are more in in of the and mammalian have of PHB proteins P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). In PHB proteins are during of are from the P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar, Kim K.H. Danner D.B. Biol. PubMed Scopus Google Scholar, S. K. J. Res. 1997; PubMed Scopus Google Scholar). might be to the lack of with of PHB proteins during cell cycle P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). 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This might during cellular to the required and of mitochondria in to energy with PHB proteins are essential during and germline The altered mitochondrial together with the in of a direct PHB deficiency and mitochondrial Although the in are are and in a of the be to be in the of the PHB In it may be that the is more in tissues that more on mitochondrial energy and in the might a stronger on The of a holdase/unfoldase protein that assembly of enzymes in mitochondrial subunits that be respiratory proteins may in the membrane and and to the membrane. may to of this together cellular metabolic The results we are with more and have body and we a in and a strong in mitochondrial At this we a in cellular metabolic for the altered in mutants PHB proteins play a more direct role in mitochondrial membrane and further in this is in support of the that lack of PHB complex might we found that are more to type PHB proteins are specifically required in situations of mitochondrial PHB are in yeast the from to growth J.L. 1997; PubMed Scopus Google Scholar). expression of PHB proteins in yeast mutants and mitochondrially encoded subunits (6Nijtmans L.G. de Jong L. Artal Sanz M. Coates P.J. Berden J.A. Back J.W. Muijsers A.O. van der Spek H. Grivell L.A. EMBO J. 2000; 19: 2444-2451Crossref PubMed Scopus (444) Google Scholar, L.G. Artal Sanz M. M. M. G.A. M. Grivell L.A. FEBS Lett. PubMed Scopus (59) Google Scholar). of mitochondrial protein to mitochondrial and gene products T. J. Biol. 1994; Full Text PDF PubMed Google Scholar). the of mitochondrial results in an in PHB protein in P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar) and in C. elegans The of the phenotype a for PHB proteins, metabolic with W.A. S. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: PubMed Scopus Google Scholar). Alternatively, might or the or of mitochondrial respiratory or the PHB from of gene expression in C. elegans G. E.L. 2000; PubMed Scopus Google Scholar) that is with expression in the as with the of expression is the larval This expression with the in in expression of is in with the of prohibitins during P.J. R. A. S.M. Cell Res. PubMed Scopus Google Scholar). and a are essential to the energy during growth and development D.B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the to has been proposed in situations of function Biochem. Biophys. Res. Commun. 2002; PubMed Scopus Google Scholar). The C. elegans for prohibitins of genes D.B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) (see for and on the it be to mutants be and to the as with the mutants D.B. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar) and to mutations growth and development. the and of on mitochondrial function from the lack of prohibitins to further the molecular of of the PHB complex and role in mitochondrial the first have the of the loss of the PHB complex of a complex multicellular organism. We demonstrate by that the mitochondrial PHB complex is essential for embryonic strongly suggesting that a PHB be We demonstrate that PHB proteins are for mitochondrial and We predict that mutations in of the genes may be for mitochondrial that have to be a molecular We J. Coates for and van der J. and R. for the van der and of H. A. laboratory are for We van for with the de Jong for and for in and and for in

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