Regulation of Mitochondrial Fusion by the F-box Protein Mdm30 Involves Proteasome-independent Turnover of Fzo1

Overview

Journal J Cell Biol

Specialty Cell Biology

Date 2006 Jun 1

PMID 16735578

Citations 61

Authors

Mafalda Escobar-Henriques

Benedikt Westermann

Thomas Langer

Affiliations

Soon will be listed here.

Abstract

Mitochondrial morphology depends on balanced fusion and fission events. A central component of the mitochondrial fusion apparatus is the conserved GTPase Fzo1 in the outer membrane of mitochondria. Mdm30, an F-box protein required for mitochondrial fusion in vegetatively growing cells, affects the cellular Fzo1 concentration in an unknown manner. We demonstrate that mitochondrial fusion requires a tight control of Fzo1 levels, which is ensured by Fzo1 turnover. Mdm30 binds to Fzo1 and, dependent on its F-box, mediates proteolysis of Fzo1. Unexpectedly, degradation occurs along a novel proteolytic pathway not involving ubiquitylation, Skp1-Cdc53-F-box (SCF) E3 ubiquitin ligase complexes, or 26S proteasomes, indicating a novel function of an F-box protein. This contrasts to the ubiquitin- and proteasome-dependent turnover of Fzo1 in alpha-factor-arrested yeast cells. Our results therefore reveal not only a critical role of Fzo1 degradation for mitochondrial fusion in vegetatively growing cells but also the existence of two distinct proteolytic pathways for the turnover of mitochondrial outer membrane proteins.

Citing Articles

E4 ubiquitin ligase promotes mitofusin turnover and mitochondrial stress response.

Anton V, Buntenbroich I, Simoes T, Joaquim M, Muller L, Buettner R Mol Cell. 2023; 83(16):2976-2990.e9.

PMID: 37595558 PMC: 10434984. DOI: 10.1016/j.molcel.2023.07.021.

Docking and stability defects in mitofusin highlight the proteasome as a potential therapeutic target.

Buntenbroich I, Anton V, Perez-Hernandez D, Simoes T, Gaedke F, Schauss A iScience. 2023; 26(7):107014.

PMID: 37416455 PMC: 10320088. DOI: 10.1016/j.isci.2023.107014.

Mitochondrial complexome reveals quality-control pathways of protein import.

Schulte U, den Brave F, Haupt A, Gupta A, Song J, Muller C Nature. 2023; 614(7946):153-159.

PMID: 36697829 PMC: 9892010. DOI: 10.1038/s41586-022-05641-w.

Schizosaccharomyces pombe Fzo1 is subjected to the ubiquitin-proteasome-mediated degradation during the stationary phase.

Ahmad F, Zhang Y, Yin H, Luo Y, Huang Y Int Microbiol. 2022; 25(2):397-404.

PMID: 35075549 DOI: 10.1007/s10123-022-00231-2.

Protein Quality Control at the Mitochondrial Surface.

den Brave F, Gupta A, Becker T Front Cell Dev Biol. 2021; 9:795685.

PMID: 34926473 PMC: 8678412. DOI: 10.3389/fcell.2021.795685.

References

Kissova I, Deffieu M, Manon S, Camougrand N . Uth1p is involved in the autophagic degradation of mitochondria. J Biol Chem. 2004; 279(37):39068-74. DOI: 10.1074/jbc.M406960200. View

Willems A, Schwab M, Tyers M . A hitchhiker's guide to the cullin ubiquitin ligases: SCF and its kin. Biochim Biophys Acta. 2004; 1695(1-3):133-70. DOI: 10.1016/j.bbamcr.2004.09.027. View

Fritz S, Weinbach N, Westermann B . Mdm30 is an F-box protein required for maintenance of fusion-competent mitochondria in yeast. Mol Biol Cell. 2003; 14(6):2303-13. PMC: 194880. DOI: 10.1091/mbc.e02-12-0831. View

Leonhard K, Herrmann J, Stuart R, Mannhaupt G, Neupert W, Langer T . AAA proteases with catalytic sites on opposite membrane surfaces comprise a proteolytic system for the ATP-dependent degradation of inner membrane proteins in mitochondria. EMBO J. 1996; 15(16):4218-29. PMC: 452147. View

Meeusen S, Nunnari J . How mitochondria fuse. Curr Opin Cell Biol. 2005; 17(4):389-94. DOI: 10.1016/j.ceb.2005.06.014. View

Uetz P, Giot L, Cagney G, Mansfield T, Judson R, Knight J . A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature. 2000; 403(6770):623-7. DOI: 10.1038/35001009. View

Neutzner A, Youle R . Instability of the mitofusin Fzo1 regulates mitochondrial morphology during the mating response of the yeast Saccharomyces cerevisiae. J Biol Chem. 2005; 280(19):18598-603. DOI: 10.1074/jbc.M500807200. View

Skowyra D, Craig K, Tyers M, Elledge S, Harper J . F-box proteins are receptors that recruit phosphorylated substrates to the SCF ubiquitin-ligase complex. Cell. 1997; 91(2):209-19. DOI: 10.1016/s0092-8674(00)80403-1. View

Tatsuta T, Langer T . Studying proteolysis within mitochondria. Methods Mol Biol. 2008; 372:343-60. DOI: 10.1007/978-1-59745-365-3_25. View

10.

Chen H, Chan D . Emerging functions of mammalian mitochondrial fusion and fission. Hum Mol Genet. 2005; 14 Spec No. 2:R283-9. DOI: 10.1093/hmg/ddi270. View

11.

Galan J, Peter M . Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc Natl Acad Sci U S A. 1999; 96(16):9124-9. PMC: 17743. DOI: 10.1073/pnas.96.16.9124. View

12.

Petroski M, Deshaies R . Function and regulation of cullin-RING ubiquitin ligases. Nat Rev Mol Cell Biol. 2005; 6(1):9-20. DOI: 10.1038/nrm1547. View

13.

Mnaimneh S, Davierwala A, Haynes J, Moffat J, Peng W, Zhang W . Exploration of essential gene functions via titratable promoter alleles. Cell. 2004; 118(1):31-44. DOI: 10.1016/j.cell.2004.06.013. View

14.

Galan J, Wiederkehr A, Seol J, Haguenauer-Tsapis R, Deshaies R, Riezman H . Skp1p and the F-box protein Rcy1p form a non-SCF complex involved in recycling of the SNARE Snc1p in yeast. Mol Cell Biol. 2001; 21(9):3105-17. PMC: 86938. DOI: 10.1128/MCB.21.9.3105-3117.2001. View

15.

Rapaport D, Brunner M, Neupert W, Westermann B . Fzo1p is a mitochondrial outer membrane protein essential for the biogenesis of functional mitochondria in Saccharomyces cerevisiae. J Biol Chem. 1998; 273(32):20150-5. DOI: 10.1074/jbc.273.32.20150. View

16.

Dimmer K, Fritz S, Fuchs F, Messerschmitt M, Weinbach N, Neupert W . Genetic basis of mitochondrial function and morphology in Saccharomyces cerevisiae. Mol Biol Cell. 2002; 13(3):847-53. PMC: 99603. DOI: 10.1091/mbc.01-12-0588. View

17.

Altmann K, Westermann B . Role of essential genes in mitochondrial morphogenesis in Saccharomyces cerevisiae. Mol Biol Cell. 2005; 16(11):5410-7. PMC: 1266436. DOI: 10.1091/mbc.e05-07-0678. View

18.

Kus B, Caldon C, Andorn-Broza R, Edwards A . Functional interaction of 13 yeast SCF complexes with a set of yeast E2 enzymes in vitro. Proteins. 2004; 54(3):455-67. DOI: 10.1002/prot.10620. View

19.

Muratani M, Kung C, Shokat K, Tansey W . The F box protein Dsg1/Mdm30 is a transcriptional coactivator that stimulates Gal4 turnover and cotranscriptional mRNA processing. Cell. 2005; 120(6):887-99. DOI: 10.1016/j.cell.2004.12.025. View

20.

Okamoto K, Shaw J . Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet. 2005; 39:503-36. DOI: 10.1146/annurev.genet.38.072902.093019. View