Mitochondria Are Mixed During Cell Division

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There is therefore a desire to redefine the SI causes the frequency of an atomic clock to of the world around us to be obtained at second in terms of an optical-clock frequency depend on its altitude. Consequently, the unprecedented resolution. Examples of such and to move away from the current definition height difference between two remote clocks investigations include testing Einstein’s theory based on caesium. But before such a redefini- can be determined by measuring their differ- of relativity at ever more stringent levels13, and tion is possible, scientists must build confi- ence in frequency. At the level of measurement searching for possible changes in the values of dence in the reproducibility of optical clocks uncertainty achieved in the latest work, clock physical constants8. Regardless of the appli- through a series of clock comparisons. The comparisons could resolve centimetre-sized cation — whether in redefining the SI second, target accuracy for these comparisons is at height differences. Therefore, clocks could surveying or fundamental physics — the better the level of parts in 1018 to clearly demonstrate provide new tools for long-term environmen- the clock comparisons, the greater the impact. the superiority of optical clocks over caesium tal monitoring of, for example, ice sheets or And with the current accuracy limits being set clocks5. ocean levels. by technical issues, rather than fundamental Clock comparisons are carried out by The BACON Collaboration demon- limits, the prospects for even better measure- measuring ratios of the optical-clock fre- strated another intriguing application of ments in the future are extremely promising. quencies using instruments called femto clock comparisons. The authors used the second-frequency combs. Until now, the best clock-frequency ratios to search for signs Rachel M. Godun is in the Department of Time comparisons between optical clocks based of possible interactions between atoms and and Frequency, National Physical Laboratory, on different atoms6–11 have been at the level dark matter — an elusive substance predicted Teddington, Middlesex TW11 0LW, UK. of parts in 1017. The BACON Collaboration to account for most of the matter in the Uni- e-mail: [email protected] presents measurements of optical-frequency verse. According to current understand- ratios reaching uncertainties at the level of ing, atoms do not interact with dark matter 18 parts in 10 , bringing the redefinition of the through electromagnetic forces. However, if 1. Boulder Atomic Clock Optical Network (BACON) SI second a step closer. these interactions were to exist, they would Collaboration. Nature 591, 564–569 (2021). 2. Brewer, S. M. et al. Phys. Rev. Lett. 123, 033201 (2019). Such frequency-ratio measurements are no cause tiny changes in atomic-clock frequen- 3. Bothwell, T. et al. Metrologia 56, 065004 (2019). mean feat, and are equivalent to determining cies. The authors detected no such changes in 4. McGrew, W. F. et al. Nature 564, 87–90 (2018). the distance from Earth to the Moon to within their experiment, but a null result is still use- 5. Riehle, F., Gill, P., Arias, F. & Robertsson, L. Metrologia 55, 188–200 (2018). a few nanometres. Therefore, exceptional ful. Combined with previous data, the finding 6. Rosenband, T. et al. Science 319, 1808–1812 (2008). care is required to control any sources of revealed that the maximum strength of any 7. Nemitz, N. et al. Nature Photon. 10, 258–261 (2016). frequency offset. The authors compared the electromagnetic interactions between atoms 8. Lange, R. et al. Phys. Rev. Lett. 126, 011102 (2021). 9. Origlia, S. et al. Phys. Rev. A 98, 053443 (2018). aluminium-ion and ytterbium clocks at NIST and a particular type of dark matter was nearly 10. Dörscher, S. et al. Metrologia 58, 015005 (2021). and the strontium clock at JILA over several ten times lower than previously determined. 11. Takano, T., Mizushima, R. & Katori, H. Appl. Phys. Express months to check reproducibility and reduce Networks of optical clocks can also be used 10, 072801 (2017). 12. Mehlstäubler, T. E., Grosche, G., Lisdat, C., Schmidt, P. O. statistical uncertainties. They found that the to explore many other aspects of physics, & Denker, H. Rep. Prog. Phys. 81, 064401 (2018). day-to-day variation in the ratios was slightly because their precision allows measurements 13. Delva, P. et al. Phys. Rev. Lett. 118, 221102 (2017). larger than expected after accounting for all known effects. This observation suggests Cell biology the existence of unknown effects, which are intrinsically hard to quantify. Nevertheless, the authors developed a statistical model to account for these uncertainties and to enable a Mitochondria are mixed rigorous assessment of the total measurement uncertainty. during cell division The BACON Collaboration used redundant elements throughout the network of optical Till Klecker & Benedikt Westermann clocks to check for any sources of bias. In particular, the authors linked the clocks at Organelles called mitochondria have essential roles in the cell NIST and JILA in two ways (Fig. 1). They used and must be inherited successfully as it divides. It turns out a 3.6-kilometre optical-fibre link — a tried- that three types of interaction with filaments of actin protein and-tested method for connecting signals between optical clocks at the required level mix and partition mitochondria during cell division. See p.659 of uncertainty. And, in what they believe to be a world first, they compared the clocks using a 1.5-km ‘free-space’ link by sending laser In 1855, the German physician Rudolf Virchow be inherited, too. On page 659, Moore et al.1 pulses through the air between NIST and JILA coined the phrase Omnis cellula e cellula — all describe this process in an unprecedented along a straight line joining the two institutes. cells come from cells. In other words, cells arise level of detail. They found that the two types of connection from the growth and division of existing cells. Two major constituents of the cytoskeleton provided a similar level of uncertainty, apart The genetic information stored in chromo (a network of proteins that determines cellu- from when data could not be obtained from somes is passed on to the next generation dur- lar architecture) are responsible for cellular the free-space link during a snowstorm. ing cell division in a highly ordered process dynamics. These are microtubules, structures The authors’ demonstration that high- called mitosis. Biologists have spent many that serve as tracks for long-distance transport accuracy clocks can be connected by free- decades deciphering the molecular choreo of organelles; and actin filaments, which medi- space links, without needing an optical-fibre graphy of this fascinating process, but much ate transport over short distances and enable infrastructure, is exciting because it opens up less attention has been given to the inheritance shape changes at the cell’s outer boundary in possibilities for applications outside the labo- of organelles called mitochondria. These are a region called the cortex. The cytoskeleton ratory, such as land surveying12. According to essential for energy metabolism and, because is drastically remodelled during cell division. Einstein’s theory of relativity, Earth’s gravity they cannot be generated de novo, they must Microtubules build a structure called the

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Cloud Cable Dividing Comet tail human cell

Mitochondrion

Actin Actin wave

Experimentally damaged mitochondrion

Figure 1 | How mitochondrial organelles are distributed during cell division. were frequently encased in what looked like a cloud of actin filaments, Moore et al.1 report three types of interaction with filaments of the protein restricting the organelles’ mobility. Some mitochondria in the waves instead actin that aid the distribution of mitochondria when human cells divide. Using had comet-tail-like structures made of actin filaments, and these organelles state-of-the-art microscopy, the authors observed that mitochondria can be moved rapidly (red arrow) in random directions. The authors tracked the fate of tethered to cable structures. It has been reported4 previously that some actin labelled mitochondria that were damaged using an experimental technique. The filaments in dividing cells form waves that revolve around the cell (black arrow) actin-mediated activities helped to mix and divide the mitochondria between in a manner reminiscent of a radar display. In these waves, the authors observed the two daughter cells during cell division, resulting in an even distribution of two types of interaction between actin and mitochondria. Mitochondria the damaged organelles. mitotic spindle that is needed to partition the detail than had been reported previously, and Mitochondria contain their own genome, chromosomes as the cell divides, and, later, found that it is independent of the presence which encodes essential proteins required actin filaments assemble a contractile ring that of actin waves. Second, within a wave, mito- for energy generation through a pathway promotes cell separation. chondria are encased by what looks like clouds called the respiratory chain (also known as Organelles are also extensively remodelled of actin filaments that seem to immobilize the electron-transport chain). If there is an during mitosis. Mitochondria often form the organelles. And third, sometimes these accumulation of mitochondria with mutations extended connected networks in human cells, clouds ‘opened’, to be followed by an aston- in the DNA that encodes such components, a and these mitochondria fragment into numer- ishing burst of mitochondrial movement. The cell’s energy production would be compro- ous small entities that lose their connection organelles were propelled by the rapid growth mised. Moreover, if a cell inherits a high load to microtubules during cell division2,3. It has (polymerization) of actin filaments. This of mitochondria with mutated DNA from its long been thought that the partitioning of generated what looks like a comet tail made mother cell, each subsequent cell division mitochondria as cells divide is a largely passive of actin. These mitochondrial movements would pass on these energy defects to the process, but this view is currently changing. were rapid, randomly oriented, and covered progeny cells. Abnormalities could therefore About ten years ago, researchers reported a substantial distances in the cell. spread to a large part of the tissue and ulti- discovery of the actin cytoskeleton in human Moore and colleagues’ observation of mately impair organ function. This possibility cells behaving unusually4. A cluster of actin actin comet tails is particularly exciting. suggests why actin dynamics might actively filaments was found to appear early during Two decades ago, it was suggested that actin contribute to the distribution of mitochondria mitosis and then to revolve in cycles through polymerization drives mitochondrial motility being inherited. the cytoplasm at a constant angular speed — in yeast cells6. However, this model is contro- Moore et al. used what are called opto time-lapse movies of cells with fluorescent versial because the transport of mitochondria genetic tools to generate cells with damaged filaments revealed circling waves (Fig. 1) into the bud that forms when yeast divides is mitochondria. The authors triggered the pro- that looked like a radar display4. Although mediated by a myosin motor protein ‘walking’ duction of damaging reactive oxygen species extremely visually striking, the function of this along actin cables7, and mitochondrial comet in a subset of mitochondria and at the same odd phenomenon had remained a mystery. tails of actin have not been documented in time specifically labelled these mitochondria. Moore et al. now shed light on this enigma. yeast. Nevertheless, movement that relies They observed that the dispersion of damaged Using cutting-edge light-microscopy technol- on actin dynamics is quite common in animal organelles depends on the presence of cycling ogy, the authors report evidence that these cells. Such processes contribute to the inter- actin waves. The authors fed their experimen- actin waves have a role in mitochondrial par- nalization of vesicles, and actin is hijacked by tal data into computer models, and the results titioning during mitosis of human cells. Like certain invading microorganisms to enable suggest that the actin waves trigger bursts of chromosomal partitioning, mitochondrial them to move in the cytoplasm of a host cell. movement driven by comet tails that randomly inheritance depends on dynamic processes The authors present stunning images of distribute mitochondria during cell division. orchestrated by the cytoskeleton — yet it turns twin actin tails emanating from the front This activity promotes organelle dispersion, out that these partitioning events occur in a of mitochondria and extending behind the and ensures that the burden of damaged completely different way. organelle, similar to the contrails left in the mitochondria is evenly split between the two The authors describe three modes of inter- sky by twin-engine aircraft. The comet tails daughter cells of the mitotic division (Fig. 1). action between mitochondria and actin during that Moore and colleagues observed were The authors’ discoveries reveal several mitosis (Fig. 1). Previous work5 suggested that often slightly twisted, and closely resemble intriguing aspects worthy of further study. It the myosin motor protein Myo19 dynamically the comet tails of actin generated by certain will be interesting to determine the molecu- tethers mitochondria to an actin network and bacteria of the genus Rickettsia that infect cells lar pathways that regulate actin dynamics on maintains the distribution of mitochondria and cause disease8. the mitochondrial surface. A previous study9 throughout the cytoplasm. First, Moore and What might be the function of these actin reported that revolving actin waves regulate colleagues observed this process in greater dynamics in mitochondrial inheritance? the balance between the division and fusion of

mitochondria during the interphase stage of Till Klecker and Benedikt Westermann are carrying two sets of 12 chromosomes. the cell cycle, which precedes mitosis. It will be at the Institute of Cell Biology, University of For rice scientists, the idea of developing important to discover whether mitochondrial Bayreuth, 95440 Bayreuth, Germany. polyploid cultivated rice is tantalizing as a movement, interconnectivity and dispersion e-mails: [email protected]; potential means for future crop improvement, are processes that mutually affect each other. [email protected] especially in the face of climate variability6. The Certain types of cell divide asymmetrically plant’s extra gene copies might enable rapid and generate daughter cells with different adaptation in response to major changes in the 1. Moore, A. S. et al. Nature 591, 659–664 (2021). fates. During the division of a stem cell, the 2. Taguchi, N., Ishihara, N., Jofuku, A., Oka, T. & Mihara, K. environment without the loss of favourable older mitochondria in the dividing cell are J. Biol. Chem. 282, 11521–11529 (2007). features7. But generating a polyploid rice from 3. Chung, J. Y., Steen, J. A. & Schwarz, T. L. Cell Rep. 16, preferentially partitioned to the daughter cell 2142–2155 (2016). a cultivated diploid plant is hugely technically that is destined to differentiate, whereas the 4. Mitsushima, M. et al. J. Cell Biol. 191, 453–462 (2010). challenging. With that in mind, Yu et al. took younger and ‘fitter’ mitochondria are appor- 5. Rohn, J. L. et al. Curr. Biol. 24, 2598–2605 (2014). an entirely different approach. The authors 6. Boldogh, I. R. et al. Proc. Natl Acad. Sci. USA 98, tioned to the daughter cell that maintains 3162–3167 (2001). started with a distant, wild polyploid cousin of 10 stem-cell properties . One can predict, there- 7. Förtsch, J., Hummel, E., Krist, M. & Westermann, B. O. sativa and O. rufipogon, and domesticated fore, that mitochondria mixing is suppressed J. Cell Biol. 194, 473–488 (2011). it using biotechnological approaches (Fig. 1). 8. Van Kirk, L. S., Hayes, S. F. & Heinzen, R. A. Infect. Immun. in these cells and that other, as yet unknown, 68, 4706–4713 (2000). The authors first spent time identifying an mechanisms ensure the asymmetric inheri- 9. Moore, A. S., Wong, Y. C., Simpson, C. L. & Holzbaur, E. L. appropriate starting strain. The ideal candi- tance of mitochondria. Clearly, mitochon- Nature Commun. 7, 12886, (2016). date needed to be amenable to callus induction 10. Katajisto, P. et al. Science 348, 340–343 (2015). drial research will yield many more surprises and regeneration — a process in which plant in the future. This article was published online on 3 March 2021. tissues are cultured to produce a mass of par- tially undifferentiated cells called a callus, from Genomics which new plants are generated. These properties are essential for gene-editing techniques. The selected individual also needed to have high biomass and tolerance to various abiotic Sowing the seeds and biotic stresses — heat and insect resistance, for example. After screening 28 polyploid wild of multi-genome rice rice lines, a strain of Oryza alta was selected, and named polyploid rice 1 (PPR1). Diane R. Wang Oryza alta has four sets of chromosomes (it is tetraploid), and is found in Central and Having more than two sets of chromosomes can help plants to South America8. The species arose as a result adapt and evolve, but generating new crops with this type of of hybridization between two ancestors that genome is challenging. A road map for doing just that has now had diploid genomes, designated C and D. The PPR1 strain selected by Yu et al. looks been developed using wild rice. quite different from cultivated O. sativa. For instance, it is very tall — more than 2.7 metres, compared with 1 metre or less for We all sometimes wish we could do more about 9,000 years ago from its wild progen- typical O. sativa. It produces abundant bio- than one thing at once — run errands, catch itor, Oryza rufipogon, through processes mass, and has broad leaves and sparse, small up on work deadlines and perhaps grab that thought to have occurred across multiple seeds adorned with awns (spiky protrusions long-overdue coffee with a friend. A genetic regions in Asia4,5. Both species are diploid, thought to aid seed dissemination). As such, state known as polyploidy helps some plant genomes to do just this. Most plants, like humans, are diploid, with two sets of every Step 1 Step 2 Step 3 Step 4 chromosome. But polyploid plants have Screening and Sequence and Genome editing for New crop roll-out selection of analysis of genome improved traits four, six or even eight sets of chromosomes. Market evaluation wild rice strains Development of and conventional These additions allow different copies of a genome-editing tools crosses gene to take on different roles, and provide

a buffer against potentially harmful muta- Field trials tions. Accordingly, polyploidy has served as a common mode of evolution in flowering plants1. Writing in Cell, Yu et al.2 outline a viable approach to producing a domesticated form of polyploid rice using gene editing. Their advance could allow us to reap the bene- fits of polyploidy in one of the world’s most important crop species. All crop species evolved from wild ancestors, Figure 1 | A fast track to cultivated polyploid rice. Yu et al.2 have developed a strategy for rapid as humans saved and propagated plants that domestication of wild polyploid rice (which has more than two sets of chromosomes, unlike the rice had favourable attributes — loss of seed- commonly grown as a food crop). The first step is to select a wild strain that has favourable characteristics dispersal mechanisms, for instance, and larger for gene editing and crop production. This is followed by genomic analysis and method optimization. 3 seeds and fruits — over hundreds or thou- Iterative cycles of genome editing, conventional crossing and testing are then needed before the new crop sands of years. The world’s main rice crop, the is rolled out to farmers and evaluated. Red highlights indicate sections of the road map completed by the Asian species Oryza sativa, was domesticated authors for the wild rice Oryza alta.