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Pathway: cardiolipin metabolic process (we have a floater!) #2

Open ValWood opened 1 week ago

ValWood commented 1 week ago

@Antonialock 's first GO-CAM!

The model http://noctua.geneontology.org/workbench/noctua-visual-pathway-editor/?model_id=gomodel%3A67086be200000363

Screenshot 2024-10-17 at 07 38 45

The genes https://www.pombase.org/results/from/id/3cf1abdc-1a95-4603-a17d-26f84425bfb8

Systematic ID Gene name Product description Budding yeast orthologs Human orthologs
SPBC26H8.11c the4 acyl-coenzyme A thioesterase The4 MRX3 THEM4,THEM5
SPAC22A12.08c crd1 cardiolipin synthase/ hydrolase fusion protein Crd1 CRD1,YKR070W CRLS1,HDHD5
SPBP18G5.02 pgs1 CDP-diacylglycerol-glycerol-3-phosphate3-phosphatidyltransferase Pgs1 PGS1 PGS1
SPAC6G10.03c cld1 mitochondrial cardiolipin-specific phospholipase Cld1 CLD1 ABHD4,ABHD5
SPBC1A4.06c tam41 mitochondrial phosphatidate cytidylyltransferase Tam41 TAM41 TAMM41
SPCC645.02 gep4 phosphatidylglycerol phosphate phosphatase Gep4 GEP4

Issues Unable to connect the4

ValWood commented 1 week ago
ValWood commented 1 week ago

Human has 17 genes annotated: @Antonialock will review human and make model

https://amigo.geneontology.org/amigo/search/bioentity?q=*%3A*&fq=regulates_closure:%22GO%3A0032048%22&sfq=document_category:%22bioentity%22

Antonialock commented 1 week ago
  • Fungal GEP4 has a functional ortholog but not true ortholog, I can't remember which phosphatase it was, we will dig that out

"Our results indicate that PTPMT1 orthologs from both Drosophila and bacteria serve as functional equivalents of GEP4 in yeast" https://pmc.ncbi.nlm.nih.gov/articles/PMC3576122/

our results demonstrate that mammalian PTPMT1 serves as a functional equivalent of GEP4 in yeast (Figure 6E). (mouse) https://pmc.ncbi.nlm.nih.gov/articles/PMC3119201/

Antonialock commented 1 week ago

"It is even questionable whether S. pombe de novo synthesized CL undergoes a FA remodeling process as there is no obvious tafazzin ortholog in this yeast (PomBase). Even though the S. pombe SPAC6G10.03c ORF is annotated in the PomBase as a mitochondrial cardiolipin-specific phospholipase Cld1 based on sequence homology with S. cerevisiae CL specific phospholipase Cld1 (Baile et al., 2014; Beranek et al., 2009), the product of the SPAC6G10.03c ORF is not involved in the CL remodeling process. Firstly, the product of the SPAC6G10.03c ORF does not localize to mitochondria (Matsuyama et al., 2006). Secondly, FA analysis of the SPAC6G10.03c deletion strain showed no difference between the wild-type strain and the strain with deletion of SPAC6G10.03c; this is something that would be expected if this potential phospholipase plays a role in the CL remodeling process (unpublished results)."

https://onlinelibrary.wiley.com/doi/full/10.1002/yea.3451

ValWood commented 1 week ago

Thats a useful review. @PCarme could you add to you list to take this review and add any other phospholipid pathways from this?

Antonialock commented 1 week ago

CLD1 mito localization is an IBA..

and if pombe doesn't do remodeling then tehre is no floater..

ValWood commented 1 week ago

So, I i) remove mitochondrion and cardiolipin from CLD1 ii) remove cardiolipin from the4? iii) get mappings fixed and add NOTs ?

Antonialock commented 1 week ago

That's what that paper would suggest, I don't know if it's controversial in any way. Do you know of anyone working on this area that you are in contact with?...

ValWood commented 1 week ago

Asking the great @snezhkaoliferenko

Snezhka, do you know anything about cardiolipin biosynthesis (i.e., does pombe do cardiolipid remodelling, see above?)? I agree that it seems unlikely that it doesn't, considering we have no taffazin. @Antonialock is not back at pombase! we were nerding last night building go-cam pathways

Antonialock commented 4 days ago

so would you remove the annotation to cardiolipin biosynthesis for tam41 or keep it? It is generally included in cartoons of CL biosynthesis, but CDP-DAG is also a precursor to other molecules (it is already annotated to CDP-DAG biosynthesis).

Antonialock commented 4 days ago

Is this positive regulation of CL biosynthesis/ just plain CL biosynthesis (without the regulation prefix ) + inner mitochondrial membrane organization?

Mieap drives formation of biological condensates (membrane less organelles, MLOs) involved in cardiolipin metabolism. Mieap BCs specifically phase separate the mitochondrial phospholipid, cardiolipin. Mieap directly binds to cardiolipin in vitro. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions in cardiolipin biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1 and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap BCs.

image

https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/

ValWood commented 4 days ago

so would you remove the annotation to cardiolipin biosynthesis for tam41 or keep it?

I'm going to remove it. It's on my to do list. I should get to it this week. I might have a couple of questions too.

snezhkaoliferenko commented 4 days ago

Wait sorry am away at conferences and teach in between so didn’t reply straightaway. Tam41 is a legit mitochondrial CDP-DG synthase. Why remove it from the cardiolipin pathway?

From: Val Wood @.> Sent: 21 October 2024 17:06 To: pombase/mitochondrion @.> Cc: Snezhana Oliferenko @.>; Mention @.> Subject: Re: [pombase/mitochondrion] Pathway: cardiolipin metabolic process (we have a floater!) (Issue #2)

so would you remove the annotation to cardiolipin biosynthesis for tam41 or keep it?

I'm going to remove it. It's on my to do list. I should get to it this week. I might have a couple of questions too.

— Reply to this email directly, view it on GitHubhttps://github.com/pombase/mitochondrion/issues/2#issuecomment-2427108418, or unsubscribehttps://github.com/notifications/unsubscribe-auth/AUYNMTZB2R3DKJNK75JRMD3Z4URB7AVCNFSM6AAAAABQC764G2VHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZDIMRXGEYDQNBRHA. You are receiving this because you were mentioned.Message ID: @.***>

ValWood commented 4 days ago

Is this positive regulation of CL biosynthesis/ just plain CL biosynthesis (without the regulation prefix ) + inner mitochondrial membrane organization?

There is a lot to pick apart here!

My knowledge about mieap is limited d to its role in nquality control i.e. Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/

Is this really demonstrating involvement in cardiolipin biosynthesis? It isn't clear to me.

They say Mieap has been reported to form vacuole-like structures, designated as Mieap-induced vacuoles (MIVs).31 To confirm this hypothesis, we performed the IF experiment on structures comprising EGFP-Mieap. EGFP-Mieap reproducibly formed green condensates, while antibodies (anti-Mieap antibody and anti-GFP antibody) produced ring-shaped staining around the green condensates (Figure S1A). Thus, we suspected that antibodies are unable to permeabilize EGFP-Mieap condensates.

Mieap condensates exhibited spherical or oval shapes, fusion, and multi-phase structure consisting of two phases: a Mieap-containing phase and a Mieap-depleted phase (Figures S1A, S1C, S1D, and Video S1). These characteristics, and their propensity to fuse, are not contradictory to a notion that Mieap condensates have liquid-like properties, suggesting that these structures are droplets.3 Therefore, we designate Mieap-induced structures as Mieap BCs (Mi-BCs).

They say there is cardiolipin in the structure, so presumably it does have some membrane properties, so are they condensates, or membrane bound?

These is also information about : Mieap prevents obesity by maintaining cristae structures of BAT presumably affecting mitochondrial membrane would also affect lipid metabolism and hence cardiolipin, but it this a regulatory mechanism, I'm not sure it is possible to know from this paper?

"In the current study, we have demonstrated a possible model of MLOs involved in CL biosynthesis and remodeling in over-expression experiments with various fluorescence-tagged proteins. However, we have not yet showed a real picture of physiological Mi-BCs in vivo. Utilizing newly developed technologies for imaging, physiological Mi-BCs must be explored and demonstrated in future study. For this purpose, it is important to establish mNeonGreen-Mieap knock-in mice to analyze endogenous Mieap protein. Furthermore, it is also critical to show that artificial Mi-BCs really contain CL metabolic enzymes and substrates/intermediates and that CL enzymatic reactions are promoted in Mi-BCs in the next study.'

I would say this is too hypothetical for GO curation right now.....

ValWood commented 4 days ago

Interesting though!

ValWood commented 4 days ago

Ah @snezhkaoliferenko sorry, the ones I am planning to remove are the4 and cld1 https://www.pombase.org/term/GO:0035965 (the ones we have annotated to 'cardiolipin remodelling') @Antonialock was that what you meant?

snezhkaoliferenko commented 4 days ago

Absolutely, the evidence is pretty flimsy

From: Val Wood @.> Sent: 21 October 2024 17:36 To: pombase/mitochondrion @.> Cc: Snezhana Oliferenko @.>; Mention @.> Subject: Re: [pombase/mitochondrion] Pathway: cardiolipin metabolic process (we have a floater!) (Issue #2)

Is this positive regulation of CL biosynthesis/ just plain CL biosynthesis (without the regulation prefix ) + inner mitochondrial membrane organization?

There is a lot to pick apart here!

My knowledge about mieap is limited d to its role in nquality control i.e. Mieap, a p53-Inducible Protein, Controls Mitochondrial Quality by Repairing or Eliminating Unhealthy Mitochondria https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/

Is this really demonstrating involvement in cardiolipin biosynthesis? It isn't clear to me.

They say Mieap has been reported to form vacuole-like structures, designated as Mieap-induced vacuoles (MIVs).31https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/#bib31 To confirm this hypothesis, we performed the IF experiment on structures comprising EGFP-Mieap. EGFP-Mieap reproducibly formed green condensates, while antibodies (anti-Mieap antibody and anti-GFP antibody) produced ring-shaped staining around the green condensates (Figure S1https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/#mmc1A). Thus, we suspected that antibodies are unable to permeabilize EGFP-Mieap condensates.

Mieap condensates exhibited spherical or oval shapes, fusion, and multi-phase structure consisting of two phases: a Mieap-containing phase and a Mieap-depleted phase (Figures S1https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/#mmc1A, S1C, S1D, and Video S1https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/#mmc3). These characteristics, and their propensity to fuse, are not contradictory to a notion that Mieap condensates have liquid-like properties, suggesting that these structures are droplets.3https://pmc.ncbi.nlm.nih.gov/articles/PMC10845071/#bib3 Therefore, we designate Mieap-induced structures as Mieap BCs (Mi-BCs).

They say there is cardiolipin in the structure, so presumably it does have some membrane properties, so are they condensates, or membrane bound?

These is also information about : Mieap prevents obesity by maintaining cristae structures of BAT presumably affecting mitochondrial membrane would also affect lipid metabolism and hence cardiolipin, but it this a regulatory mechanism, I'm not sure it is possible to know from this paper?

"In the current study, we have demonstrated a possible model of MLOs involved in CL biosynthesis and remodeling in over-expression experiments with various fluorescence-tagged proteins. However, we have not yet showed a real picture of physiological Mi-BCs in vivo. Utilizing newly developed technologies for imaging, physiological Mi-BCs must be explored and demonstrated in future study. For this purpose, it is important to establish mNeonGreen-Mieap knock-in mice to analyze endogenous Mieap protein. Furthermore, it is also critical to show that artificial Mi-BCs really contain CL metabolic enzymes and substrates/intermediates and that CL enzymatic reactions are promoted in Mi-BCs in the next study.'

I would say this is too hypothetical for GO curation right now.....

— Reply to this email directly, view it on GitHubhttps://github.com/pombase/mitochondrion/issues/2#issuecomment-2427173026, or unsubscribehttps://github.com/notifications/unsubscribe-auth/AUYNMT744RX7CI44XVVMGA3Z4UUPNAVCNFSM6AAAAABQC764G2VHI2DSMVQWIX3LMV43OSLTON2WKQ3PNVWWK3TUHMZDIMRXGE3TGMBSGY. You are receiving this because you were mentioned.Message ID: @.***>

Antonialock commented 2 days ago

Ah @snezhkaoliferenko sorry, the ones I am planning to remove are the4 and cld1 https://www.pombase.org/term/GO:0035965 (the ones we have annotated to 'cardiolipin remodelling') @Antonialock was that what you meant?

we did discuss whether pombe does cardiolipin remodeling (we were not sure) We additionally discussed whether cardiolipin remodeling starts following CDP-DAG biosynthesis (which is also a precursor to e.g. PI) with CDP-DAG biosynthesis (most cartoons include tam41 in this pathway)

ValWood commented 2 days ago

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