Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division

Cho, Bongki; Cho, Hyo Min; Jo, Youhwa; Kim, Hee Dae; Song, Myoungjae; Moon, Cheil; Kim, Hyongbum; Kim, Kyungjin; Sesaki, Hiromi; Rhyu, Im Joo; Kim, Hyun; Sun, Woong

doi:10.1038/ncomms15754

Cited by 136 publications

(141 citation statements)

References 72 publications

(118 reference statements)

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“…As further evidence for excess membrane tension, we observed pearling modes on 11% of dividing mitochondria (N=88) (SFig. 9e), also previously reported in neuronal mitochondria [39,40]. We found that mitochondria exhibiting pearling modes eventually underwent fission of at least one of the constriction sites (100%, N=10).…”

Section: Fission Events Are Characterized By Increased Membrane Tensionsupporting

confidence: 84%

“…Furthermore, increases in Ca2+ leading up to mitochondrial division [12,40,54] SIM images were reconstructed using a custom 2D linear SIM reconstruction software obtained at Janelia farm, as previously described [58,59]. Images were reconstructed using a generalized Weiner filter parameter value of 0.02-0.05 with background levels of ~100.…”

Section: Mitochondrial Fission Differs From Other Fission Processes Smentioning

confidence: 99%

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Mitochondrial membrane tension governs fission

Mahecic

Carlini

Kleele

et al. 2018

Preprint

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2Mitochondria rely on cellular machinery for their division, which is an essential component of metabolic response of the cell. Many division factors have been identified; however, a framework accounting for the energetic requirements of the mitochondrial fission process is lacking. We report that the presence of an active constriction does not ensure fission. Instead, by measuring constrictions down to ~100 nm with time-lapse super-resolution microscopy, we found that 34% of constrictions failed to divide and 'reversed' to an unconstricted state. Higher local curvaturesreflecting an increased bending energy -made constriction sites more likely to divide, but often with a significant residual energy barrier to fission. Our data suggest that membrane tension, largely arising from pulling forces, could account for this missing energy. These results lead us to propose that mitochondrial fission is probabilistic, and can be modeled as arising from bending energy complemented by a fluctuating membrane tension.Mitochondria are highly dynamic organelles, transported through the cytoplasm along cytoskeletal networks as they change in size and shape. Mitochondrial morphologies can range from a filamentous, connected network to a fragmented collection of individuals. Underlying such morphological changes are altered equilibria between fusion and division 1,2 . These transformations have been linked to an adaptive response to cellular energy requirements, for example in response to stress [3][4][5] or the cell cycle 6 . As a vestige of their bacterial origins, mitochondria cannot be generated de novo, but must multiply by division, or fission, of existing mitochondria 7 . Division has also been suggested to act as part of a quality control mechanism 8,9 and an intracellular signal for mitophagy 10,11 .All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/255356 doi: bioRxiv preprint first posted online 3 In bacterial division systems, internal assembly of the fission machinery is tightly regulated and a series of cell cycle checkpoints ensure daughter cell viability. In contrast, the mitochondrial division machinery is external to the organelle, allowing cells to flexibly regulate fission. Initially, the division site is marked by a pre-constriction defined by contact with ER tubules 12 and deformed by targeted actin polymerization [13][14][15] Live-cell Structured Illumination Microscopy (SIM) of Drp1-mediated mitochondrial constriction events enabled us to measure dynamic changes in membrane geometry leading up to and following division. We discovered that a fraction of mitochondria constrict dramatically before relaxing to an unconstricted state, termed 'reversals'. Using a custom-written image analysis package and classical elasticity theory, we calculated the energy differences between fission and reversal events, which al...

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Section: Fission Events Are Characterized By Increased Membrane Tensionsupporting

confidence: 84%

Section: Mitochondrial Fission Differs From Other Fission Processes Smentioning

confidence: 99%

Mitochondrial membrane tension governs fission

Mahecic

Carlini

Kleele

et al. 2018

Preprint

View full text Add to dashboard Cite

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“…In light of the monophyletic origin of mitochondria, we and others postulated that metazoan mitochondria would also harbour a fission machinery located in the matrix 8,22 . Indeed, fission of the matrix compartment has been observed in the absence of outer membrane fission in several metazoans 23–26 . However, previous attempts at bioinformatic identification of a bacteria-derived division machinery in metazoan mitochondria based on sequence similarity have failed 10,27 .…”

Section: Introductionmentioning

confidence: 99%

Bacterial FtsZ induces mitochondrial fission in human cells

Spier

Sachse

Tham

et al. 2020

Preprint

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32Mitochondria are key eukaryotic organelles that evolved from an intracellular bacterium, 33 in a process involving bacterial genome rearrangement and streamlining. As 34 mitochondria cannot form de novo, their biogenesis relies on growth and division. In 35 human cells, mitochondrial division plays an important role in processes as diverse as 36 mtDNA distribution, mitochondrial transport and quality control. Consequently, defects 37 in mitochondrial division have been associated with a wide range of human pathologies. 38While several protists have retained key components of the bacterial division machinery, 39 none have been detected in human mitochondria, where the dynamin-related protein 40 Drp1, a cytosolic GTPase is recruited to the mitochondrial outer membrane, forming 41 helical oligomers that constrict and divide mitochondria. Here, we created a human codon 42 optimized version of FtsZ, the central component of the bacterial division machinery, and 43 fused it to a mitochondrial targeting sequence. Upon expression in human cells, mt-FtsZ 44 was imported into the mitochondrial matrix, specifically localizing at fission sites prior to 45Drp1 and significantly increasing mitochondrial fission levels. Our data suggests that 46 human mitochondria have an internal, matrix-localized fission machinery, whose 47 structure is sufficiently conserved as to accommodate bacterial FtsZ. We identified 48 interaction partners of mt-FtsZ, and show that expression of PGAM5, FAM210, SFXN3 and 49 MTCH1 induced mitochondrial fission. Our results thus represent an innovative approach 50 for the discovery of novel critical mitochondrial fission components. 51 52 53

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“…with cholesterol in the IMM (Gerhold et al, 2015) . Additionally, mammalian cell culture 522 models show that constriction of the IMM is an important early step in mitochondrial fission 523 (Cho et al, 2017), and preferentially occurs where the replicating mtDNA nucleoid is located 524 (Lewis, Uchiyama and Nunnari, 2016). The morphological and physiological defects we 525 observed upon loss of twnk-1 may imply that, in C. elegans, Twinkle serves as an IMM protein 526…”

mentioning

confidence: 99%

Twinkle is not the mitochondrial DNA replicative helicase in C. elegans, but may have alternate mitochondrial functions

Henderson

Euro

Suomalainen

et al. 2019

Preprint

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Twinkle is not the mtDNA helicase in C. elegans 17 ABSTRACT 26 27 Dysfunction of mitochondrial DNA replication machinery is a common cause of mitochondrial 28 diseases. The minimal mammalian replisome is made up of DNA polymerase gamma, replicative 29 helicase Twinkle, and single-stranded DNA binding protein. The replisome is localized to the 30 inner mitochondrial membrane and serves as the site of mitochondrial DNA replication and 31 mitochondrial fission. Recently, a sequence homolog of Twinkle was uncovered in the nematode 32 Caenorhabditis elegans. Here, we characterized this homolog, twnk-1, and report that twnk-1 33 does not function as the primary mitochondrial DNA replicative helicase in this species, as loss 34 of twnk-1 does not result in reduce mitochondrial DNA levels, or result in other expected 35 mitochondrial dysfunctions such as reduced oxygen consumption rates, increased sensitivity to 36 metabolic perturbations, or reduced muscle function. Instead, twnk-1 mutants have increased 37 mitochondrial DNA as they age, and exhibit phenotypes associated with mitochondrial stress, 38 including reduced fecundity, an activation of the mitochondrial unfolded protein response, and 39 mitochondrial fragmentation. Our results suggest in Caenorhabditis elegans, twnk-1 does not 40 function as the mitochondrial DNA replicative helicase, but has an alternative function in 41 regulating mitochondrial function. 42 43 45Mitochondria are essential organelles, responsible for cellular energy production and 46 the synthesis of metabolites in metazoa. They are the site of β-oxidation of fatty acids and 47 oxidative phosphorylation, have essential roles in calcium homeostasis and apoptosis, and drive 48 anabolic biosynthesis events that support cellular growth. Aberrant mitochondrial function can 49 trigger a wide range of metabolic consequences, and mitochondrial dysfunction is associated 50 with numerous diseases (Gorman et al.

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Constriction of the mitochondrial inner compartment is a priming event for mitochondrial division

Cited by 136 publications

References 72 publications

Mitochondrial membrane tension governs fission

Mitochondrial membrane tension governs fission

Bacterial FtsZ induces mitochondrial fission in human cells

Twinkle is not the mitochondrial DNA replicative helicase in C. elegans, but may have alternate mitochondrial functions

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