Regulation of mitochondrial translation in...
Transcript of Regulation of mitochondrial translation in...
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Regulation of mitochondrial translation in yeasts
Nathalie BonnefoyMeetochondrie 2017
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• Basic processes are conserved
• Facultative aerobe -> powerful selection tool
Yeasts are useful models for mitochondrial studies
glucose CO2 + H2O
O2fermentation
wild-type respiratorymutant
mtDNA
respirationethanol
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• Basicprocessesareconserved
• Facultativeaerobe->powerfulselectiontool
• Geneticallyversatile
• MitochondrialtransformationisavailableinbuddingyeasttomanipulatethemtDNA ->reportergenefortranslation
• Manyfeaturesareclosertomammaliancells(mRNAstructure,factors)infissionyeast
Yeasts are useful models for mitochondrial studies
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S.pombeS.cerevisiae H.sapiens
Conservationofgeneraltranslationfactors
+/- + +
Transcriptionunits 11 2 3
tRNA punctuation - + +
5’UTRofmRNA Long Veryshort Generallynone
SizeofmtDNA 75-85kb 19kb 16kb
Introncontent 13atmost 4atmost -
S. pombe is an excellent model to studymitochondrial gene expression
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• Dualgeneticorigin,specificcode
• Inter-dependenceandcouplingwithotherstepsofmt geneexpression
• Hydrophobicityofmostmt-encodedproteinsrequiresco-insertion
• Assemblyofmostmt-encodedproteinswithnuclear-encodedsubunitstoformtheRCcomplexes->needofconcertation
• Unconventionalandpoorlyunderstoodstartsiteselection
• mt-mRNAuntranslatedregionsvaryalotamongstorganisms
Mitochondrial translation presents many specific features and constraints
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Regulation of mitochondrial translation
Any process that modulates the frequency, rateor extent of the chemical reactions and pathwaysresulting in the formation of proteins by thetranslation of mRNA in a mitochondrion.
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• Adjustthestoichiometryofthedifferentsubunits• Adapttoavailabilityofcofactors• Respondtoenergeticneeds• Sub-localizesynthesiswheresubunitsareneeded• Coordinatemt synthesiswiththesupplyofnuclear-encodedsubunits
• Thisoptimizationallowsto:Ø Protectmitochondriafromtheoverabundanceofmt-encodedproteinsØ Preventthetoxicaccumulationofnuclear-encodedproteinsatthe
surfaceofthemembrane
Regulation of mitochondrial translation is necessary
Mt-mRNA areabundant andthere is little regulation atthetranscriptionlevel.Translationregulation is needed to:
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• Adjustthestoichiometryofthedifferentsubunits• Adapttoavailabilityofcofactors• Respondtoenergeticneeds• Sub-localizesynthesiswheresubunitsareneeded• Coordinatemt synthesiswiththesupplyofnuclear-encodedsubunits
• Thisoptimizationallowsto:Ø Protectmitochondriafromtheoverabundanceofmt-encodedproteinsØ Preventthetoxicaccumulationofnuclear-encodedproteinsatthe
surfaceofthemembrane
Regulation of mitochondrial translation is necessary
Mt-mRNA areabundant andthere is little regulation atthetranscriptionlevel.Translationregulation is needed to:
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• Cis-elements inmRNAØ e.g. Stem-loop structureinCox2
• RibosomeitselfØ e.g. Ribsomal subunit isoforms,post-translational modifications
• GeneraltranslationfactorsØ e.g. RRF,IF3
• mRNA specific translational activatorsØ Bona fideØ Dualfunction ->link with other steps
• Generalrepressors oftranslationØ e.g. Ppr5,PTCD1
• Micro-RNAs?
Actors of mt translation regulation
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• Cis-elements inmRNAØ e.g. Stem-loop structureinCox2
• RibosomeitselfØ e.g. Ribsomal subunit isoforms
• GeneraltranslationfactorsØ e.g. RRF,IF3
• mRNA specific translational activatorsØ Bona fideØ Dualfunction ->link with other steps
• Generalrepressors oftranslationØ e.g. Ppr5,PTCD1
• Micro-RNAs?
Actors of mt translation regulation
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Aep1Aep2
ATP9
Atp22Nca2?Nca3?
ATP8/6
Pet54Pet122Pet494
COX3
Pet111COX2
Mam33Pet309Mss51
COX1
Cbp1Cbs1Cbs2Cbp3Cbp6
CYTb
FactorTargetmRNA
Budding yeast translational activators
VAR1 Sov1
• Allmt-mRNA areconcerned• mRNA stableinmutant,protein absent• Low abundance• Bona fide activators act onthe5’UTRonly• Some areRNAbindingproteins• Poorly conserved inevolution• Mediate several typesofinteractions:with
themRNA,themembrane,theribosome,other activators orcofactors
Startsiteselection
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Cox2
Cox1
Cox3
Cit1
Cox4
Cox3/Atp6
Var1Cox1
Cox2Cytb
Role in limiting translation: overexpression of Pet111, the COX2 translational activator,
inhibits Cox1 synthesis
Fiorietal.,Mol Microb 2005
Mtproteinsynthesis Mtproteinsteadystate
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Role in adaptation to respiratory switch: Mam33 functions to provide enough Cox1 in
glucose for a rapid adaptation to non-fermentable carbon sources
Roloff andHenry,Mol.Biol.Cell,2015
Mtproteinsynthesis
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Role in coupling translation and assembly: In yeast, optimal assembly of the three
complexes is regulated in a different way by translation activators
Cytb incomplexIII:Cbp3/Cbp6
Atp6incomplexV:Atp22
Cox1incomplexIV:Mss51
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Cbp1Cbs1Cbs2 Cbp3Cbp6
CYTb
FactorTarget mRNA
Efficient synthesis of Cytb requiresribosome-bound Cbp3-Cbp6 complex
CYTbmRNACYTbmRNA
Cbp3
Cytb
Cbp3Cbp6 Cbp6
complex III
Gruschke etal.J.CellBiol.2010
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CYTbmRNA InteractionTuckeretal.PLOSGenet2013
Human UQCC1 and UQCC2 form a complex thatinteracts with CYTb and is essential for translation
and/or immediate stability
Mtproteinsynthesis
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Atp22Nca2?Nca3?
ATP8/6
FactorTargetmRNA
Synthesis of Atp6 is dependent upon free F1
Rak etal.,Mol Biol Cell2016
b a F1
F0
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In human the lack of F1 regulates Atp6 stabilityrather than translation
Rak etal.FEBSlett 2011
Hela Hela–sh F1b
Mtproteinsynthesis
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xx
x
x
Mss51 interacts with the nascent Cox1 protein to mediate its assembly and
feedback regulation
AfterOtt andHerrmann,2010
Mam33Pet309Mss51
COX1
FactorTargetmRNAMam33
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xx
x
x
Mss51 interacts with the nascent Cox1 protein to mediate its assembly and
feedback regulation
Mam33 wt
∆cox14
∆pet191∆cox14
Cox1
A
T
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Mss51balance Strain TranslationofCOX1
Assembly ofcomplex IV
The equilibrium between the Translation and Assembly forms of Mss51 modifies synthesis of Cox1
wt
Assemblydefect
T A
AT
TA
++ ++
+/- -
+/-++∆cox14
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xx
x
x
Mss51 interacts with the nascent Cox1 protein to mediate its assembly and
feedback regulation
AfterOtt andHerrmann,2010
Mam33
Heme b Heme aT
A
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Mss51balance Strain TranslationofCOX1
Assembly ofcomplex IV
The equilibrium between the Translation and Assembly forms of Mss51 modifies synthesis of Cox1
wt
Assemblydefect
T A
AT
TA
++ ++
+/- -
+/-++∆cox14Lowheme bMss51hememutant
+/- +/-
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An increase of Cox1 and Cytb synthesis in ∆rrf1 cells depends on the specific
translational activators
Cox1--Var1
mtEF-G2
mtRRF1
Ostojic etal.,Nuc.AcidsRes.2017
Mtproteinsynthesis
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kDa
Mss51A
Mss51T
- 440
- 232
- 140
wt ∆rrf1
BN-PAGE-Digitonin
Tom40
Deletion of rrf1 does not modify Mss51 accumulation but increases the proportion of the Mss51T complex
Ostojic etal.,Nuc.AcidsRes.2017
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Mss51balance Strain TranslationofCOX1
Assembly ofcomplex IV
The equilibrium between the Translation and Assembly forms of Mss51 modifies synthesis of Cox1
wt
Assemblydefect
T A
AT
TA
++ ++
+/- -
+/-++∆cox14lowheme b +/- +/-
+++ +/-∆rrf1
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Deletion of the 15 last residues of Cox1 abolishes the feedback regulation
Maybealsoaroleinassemblyandsuper-complexformation…
Garcia-Villegasetal.,J.Biol.Chem.2017
Cox1
Mtproteinsynthesis
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Mss51balance Strain TranslationofCOX1
Assembly ofcomplex IV
The equilibrium between the Translation and Assembly forms of Mss51 modifies synthesis of Cox1
wt
Assemblydefect
T A
AT
TA
++ ++
+/- -
+/-++∆cox14lowheme b +/- +/-
+++ +/-∆rrf1COX1-∆C15 +++ ++
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Conservation of Cox1 translational activators in yeasts and human
S.cerevisiae S.pombe H.sapiensName Role Name Role Name Role Disease
Pet309 Cox1synthesis Ppr4 Cox1Synthesis
LRPPRC AllmRNA,stabilization
…
LateonsetLeigh’s
syndromeMam33 Cox1 synthesis
inglucoseMam33 ? P32/
C1QBPNumerous?Chaperone
Cardio-myopathy(mice)
Mss51 Cox1 synthesisFeedback
Heme sensing
Mss51 StabilityofCox1
MSS51 ?Muscleprotein
-
YGR021w ? SPBC8D2.12c
? TACO1 SynthesisofCox1
LateonsetLeigh’s
syndrome
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Mt-mtRNAs
cox1
21S
Cox1Cytb
Cox2
Atp6
Rps3
Cox3
Atp9
Kühl etal.Nucl.Acids Res.2011
Ppr4 is the first mRNA-specific translationalactivator in S. pombe mitochondria
Mtproteinsynthesis
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Conservation of Cox1 translational activators in yeasts and human
S.cerevisiae S.pombe H.sapiensName Role Name Role Name Role Disease
Pet309 Cox1synthesis Ppr4 Cox1Synthesis
LRPPRC AllmRNA,stabilization
…
LateonsetLeigh’s
syndromeMam33 Cox1 synthesis
inglucoseMam33 ? P32/
C1QBPNumerous?Chaperone
Cardio-myopathy(mice)
Mss51 Cox1 synthesisFeedback
Heme sensing
Mss51 StabilityofCox1
MSS51 ?Muscleprotein
-
YGR021w ? SPBC8D2.12c
? TACO1 SynthesisofCox1
LateonsetLeigh’s
syndrome
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TACO1 is the first mRNA-specific translationalactivator in human mitochondria
Mtproteinsynthesis
Weraarpachai etal.Nat.Genet.2009
Mt-mRNA
COX1
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TACO1 binds the COX1 mRNA, mostly at the 5’ end
Richmanetal.Nat.Com.2016
COX1
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Conservation of Cox1 translational activators in yeasts and human
S.cerevisiae S.pombe H.sapiensName Role Name Role Name Role Disease
Pet309 Cox1synthesis Ppr4 Cox1Synthesis
LRPPRC AllmRNA,stabilization
…
LateonsetLeigh’s
syndromeMam33 Cox1 synthesis
inglucoseMam33 ? P32/
C1QBPNumerous?Chaperone
Cardio-myopathy(mice)
Mss51 Cox1 synthesisFeedback
Heme sensing
Mss51 StabilityofCox1
MSS51 ?Muscleprotein
-
YGR021w ? SPBC8D2.12c
? TACO1 SynthesisofCox1
LateonsetLeigh’s
syndrome
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Bourens andBarrientos,EMBOreports2017
MITRAC is a COX1 pre-assembly complex equivalent to the yeast COX1-COA3-COX14 complex
C12ORF62:COX14MITRAC12:COA3MITRAC15:COA1MITRAC7/C12ORF52
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Micketal.Cell2012;
For some authors, MITRAC couples optimal complex IV assembly and translation regulation of COX1
Optimalassembly
Feedbackregulation
Adaptationofmt-synthesistoinfluxofnc-encodedproteins
Micketal.Cell2016
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Bourens andBarrientos,EMBOreports2017
For others, COX1 synthesis and formation of the CMC1-COX1-COA3-COX14 complex are not impaired
by downstream defects in CIV biogenesis
Mtproteinsynthesis
Mtproteinsteadystate
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Mt translation work
• Translational activators: T.D. Fox, A. Tzagoloff
• General translation factors: L. Spremulli
• Feedback regulation: A. Barrientos, T.D. Fox, D. Winge, X. Perez-Martinez
• MITRAC: P. Rehling, A. Barrientos
• PPR proteins: A. Filipovska, X. Perez-Martinez
• Ribosome: J. Herrmann, Martin Ott, Alexey Amunts
• For some of our data: G Dujardin, CJ Herbert, C panozzo, A Bourand-Plantefol, J Ostojic, I Kühl
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• Cis elements: Are there some regulating mt translation in human mtRNA? -> Would make sense since untranslated regions are limited
• Ribosome: Role in start site selection? Specificity of ribosomes for translation of RC subunits? Effect of post-translational modifications?
• General factors: Could the phenotype of e.g. RRF and IF3 disease be an assembly defect?
• Translational activators: are they more bona fide translational activators in human? Does MITRAC really play a role in translational control?
• Translation inhibitors: Are Ppr5 and PTCD1 functionning similarly? Are theyother general or specific negative regulators in human, like Smt1?
• Non coding micro-RNA: To what extent nuclear and mitochondria-encodedmiRNA regulate mt translation?
Open questions