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Bacterial FtsZ induces mitochondrial fission in human cells

Anna Spier, Martin Sachse, Nam To Tham, Mariette Matondo, Pascale Cossart, Fabrizia Stavru

Preprint posted on January 24, 2020 https://www.biorxiv.org/content/10.1101/2020.01.24.917146v1.full

Does the mitochondrial inner membrane possess a unique fission machinery? Spier et al. show that FtsZ, which is a protein responsible for bacterial division, induces mitochondrial inner-membrane fission when expressed in human mitochondria.

Selected by Leeba Ann Chacko

Background:

Mitochondria are dynamic tubular organelles that constantly undergo fission and fusion events inside the cell. These dynamics are regulated by specific proteins. For instance, fusion of the mitochondrial outer membrane (OMM) is regulated by mitofusin 1 and mitofusin 2 (MFN1 and MFN2) while fission is mediated by the dynamin-related protein 1 (DRP1). Likewise, fusion of the inner mitochondrial membrane (IMM) is brought about by the dynamin-like GTPase optic atrophy 1 (OPA1)1. Interestingly, how IMM fission occurs remains elusive. Two IMM proteins, namely, MTP18 and S-OPA1 have shown to affect mitochondrial morphology, however, the mechanism through which they induce mitochondrial fission is not well understood2. Spier et al.  address this question by looking at the evolutionary past of mitochondria for clues.

Today, it is widely accepted that mitochondria do not form de novo and evolved from a proteobacterial lineage3. It has been shown that some of these proteobacteria possess inner membrane invaginations similar to what is seen in mitochondrial cristae. Several unicellular eukaryotes have a mitochondrial FtsZ4 , however, the division machinery of mitochondria in metazoan or fungal cells involving DRP1 is not like what is observed in bacteria involving the Z-ring forming protein, FtsZ5,6. This suggests that there is no evolutionary conservation of the division machinery between the bacteria and mitochondria of opistokonts (fungi and metazoan). To test whether human mitochondria have completely lost their ancestral bacterial division machinery, Spier et al. introduced a human codon-optimized version of FtsZ (mt-αFTsZ) with the ability to be targeted to mitochondria inside human cells. Interestingly, the authors found that not only did the mt-αFTsZ protein localize to the mitochondrial matrix before DRP1 bound to the OMM, but mt-αFTsZ also increased mitochondrial fission events in the cell. The authors’ findings led to the discovery of novel proteins that associate with mt-αFtsZ, suggesting the presence of a unique IMM fission machinery.

Key findings:

1. Proteobacterial FtsZ punctae localize to mitochondrial matrix constrictions and induce fission

The authors observed that the human codon-optimized version of Ftsz (mt-αFtsZ) expressed inside cells formed punctae that localized to mitochondrial matrix constrictions. The C-terminus of mt-αFtsZ was essential for its ability to localize to the IMM and induce fission. Using electron microscopy, the authors showed that the expression of mt-αFtsZ inside cells did not affect the ultrastructure of the mitochondrial constrictions. The authors also showed that the expression of full-length mt-αFtsZ induced mitochondrial fission.

2. mt-αFtsZ localizes to mitochondrial matrix constructions before DRP1 is recruited to the OMM

Through live-cell imaging, the authors observed that all fission sites contained mt-αFtsZ and these punctae distributed to the tips of the daughter mitochondria upon abscission. Additionally, the authors showed that the full-length mt-αFtsZ punctae are recruited to matrix constriction sites before the recruitment of DRP1 on the outer mitochondrial membrane during mitochondrial fission, thus, suggesting that matrix constrictions occur before DRP1-mediated outer mitochondrial membrane scission.

3. mt-αFtsZ localization to the IMM is independent of the replication of the mitochondrial nucleoid

The authors found that the mt-αFtsZ punctae and the mitochondrial nucleoids, for the most part, do not co-localize with each other. To test whether the small co-localizing subset contained replicating nucleoids, the authors labeled actively replicating mtDNAs and found that they also do not colocalize with mt-αFtsZ punctae.  Upon inhibiting mtDNA replication using dideoxycytosine (ddC), the nucleoid packing protein localized to the entire matrix instead of just the nucleoids. However, in the presence of ddC, the localization of mt-αFtsZ was unaffected suggesting that mt-αFtsZ localization is independent of nucleoid replication.

4. Four candidate proteins were identified as effectors of inner mitochondrial membrane fission

To identify the players involved in IMM fission, the authors identified the interaction partners of mt-αFtsZ using an immunoprecipitation approach and quantitative mass spectrometry. Using gene ontology analysis, the authors were able to narrow down on five highly enriched mitochondrial inner membrane proteins, namely the mitochondrial serine-threonine phosphatase PGAM5, MTCH1 (mitochondrial carrier homolog 1), FAM210A, the ATP synthase membrane subunit DAPIT (diabetes-associated protein in insulin-sensitive tissue) and SFXN3 (Sideroflexin 3). Four of the five proteins expressed inside cells localized at matrix constrictions and induced mitochondrial fission. However, silencing these proteins did not induce mitochondrial fusion. Thus, the authors identified PGAM5, MTCH1, FAM210A, and SFXN3 as putative effectors of IMM fission.

What I liked about this preprint:

Whenever I have thought about mitochondrial fission, only the ER constriction with actin and DRP1 mediated fission mechanism would come to mind. Therefore, when I came across this preprint which proposed a fission machinery that occurs prior to DRP1-mediated fission, I was immediately curious to know more. Upon finding out that the bacterial fission machinery can induce mitochondrial fission, I was quite excited. The authors have not only alluded to the existence of an inner membrane fission machinery that shares structural features with the bacterial fission machinery, they have also opened doors to further understand the evolutionary past of mitochondria.

Questions for the authors:

1. Two inner membrane proteins namely, S-OPA1 and MTP18 induce mitochondrial fission when expressed in cells. Additionally, MTP18 depletion causes mitochondria to hyperfuse.

A) Were these proteins identified as interacting partners of mt-αFtsZ?

B) Do you think that S-OPA1 and MTP18 could also be involved in the IMM fission machinery that you have described?

2. You show that the expression of mt-αFtsZ induces mitochondrial fragmentation and you also show that mt-αFtsZ action precedes that of DRP1. Given that individually silencing the four effectors of IMM fission did not affect mitochondrial morphology, do you think the IMM machinery is essential for DRP1 mediated mitochondrial fission? Would introducing mt-αFtsZ in cells devoid of DRP1 still induce mitochondrial fission?

References:

  1. Sprenger, H.-G., & Langer, T. (2019). The Good and the Bad of Mitochondrial Breakups. Trends in Cell Biology, 29(11), 888–900. http://doi.org/https://doi.org/10.1016/j.tcb.2019.08.003
  2. Wai, T., & Langer, T. (2016). Mitochondrial Dynamics and Metabolic Regulation. Trends in Endocrinology & Metabolism, 27(2), 105–117. http://doi.org/https://doi.org/10.1016/j.tem.2015.12.001
  3. Martijn, J., Vosseberg, J., Guy, L., Offre, P., & Ettema, T. J. G. (2018). Deep mitochondrial origin outside the sampled alphaproteobacteria. Nature, 557(7703), 101–105.
  4. Leger, M. M., Petrů, M., Žárský, V., Eme, L., Vlček, Č., Harding, T., et al. (2015). An ancestral bacterial division system is widespread in eukaryotic mitochondria. Proc Natl Acad Sci USA, 112(33), 10239.
  5. Kraus, F., & Ryan, M. T. (2017). The constriction and scission machineries involved in mitochondrial fission. Journal of Cell Science, 130(18), 2953–2960. http://doi.org/10.1242/jcs.199562
  6. Szwedziak, P., Wang, Q., Bharat, T. A. M., Tsim, M., & Löwe, J. (2014). Architecture of the ring formed by the tubulin homologue FtsZ in bacterial cell division. eLife, 3, e04601. http://doi.org/10.7554/eLife.04601

Tags: bacteria, cell biology, evolution, fission, ftsz, mitochondria

Posted on: 24th February 2020 , updated on: 28th February 2020

doi: https://doi.org/10.1242/prelights.17106

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  • Author's response

    Fabrizia Stavru shared

    1. Two inner membrane proteins namely, S-OPA1 and MTP18 have are known to induce mitochondrial fission when expressed in cells. Additionally, MTP18 depletion causes mitochondria to hyperfuse. 

    A) Were these proteins identified as interacting partners of mt-αFtsZ? 

    MTP18 was identified and is mentioned in the preprint as  MTFP1 (its other name). We did not identify Opa1.

    B) Do you think that S-OPA1 and MTP18 could also be involved in the IMM fission machinery that you have described? 

    Yes, it’s possible. Future experiments will tell

    2. You show that the expression of mt-αFtsZ induces mitochondrial fragmentation and you also show that mt-αFtsZ action precedes that of DRP1. Given that individually silencing the four effectors of IMM fission did not affect mitochondrial morphology, do you think the IMM machinery is essential for DRP1 mediated mitochondrial fission? 

    I do think so. To the fact that silencing the candidates did not induce hyperfusion: it could be that they are redundant. Silencing multiple candidates was toxic. Alternatively, the candidates we presented here are involved, but more peripherally, i.e. it could be that among the list there are candidates with more striking effects.

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