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Mitochondria are mixed during cell division

Organelles called mitochondria have essential roles in the cell and must be inherited successfully as it divides. It turns out that three types of interaction with filaments of actin protein mix and partition mitochondria during cell division.

In 1855, the German physician Rudolf Virchow coined the phrase Omnis cellula e cellula — all cells come from cells. In other words, cells arise from the growth and division of existing cells. The genetic information stored in chromosomes is passed on to the next generation during cell division in a highly ordered process called mitosis. Biologists have spent many decades deciphering the molecular choreography of this fascinating process, but much less attention has been given to the inheritance of organelles called mitochondria. These are essential for energy metabolism and, because they cannot be generated de novo, they must be inherited, too. Writing in Nature, Moore et al.1 describe this process in an unprecedented level of detail.

Two major constituents of the cytoskeleton (a network of proteins that determines cellular architecture) are responsible for cellular dynamics. These are microtubules, structures that serve as tracks for long-distance transport of organelles; and actin filaments, which mediate transport over short distances and enable shape changes at the cell’s outer boundary in a region called the cortex. The cytoskeleton is drastically remodelled during cell division. Microtubules build a structure called the mitotic spindle that is needed to partition the chromosomes as the cell divides, and, later, actin filaments assemble a contractile ring that promotes cell separation.

Organelles are also extensively remodelled during mitosis. Mitochondria often form extended connected networks in human cells, and these mitochondria fragment into numerous small entities that lose their connection to microtubules during cell division2,3. It has long been thought that the partitioning of mitochondria as cells divide is a largely passive process, but this view is currently changing.

About ten years ago, researchers reported a discovery of the actin cytoskeleton in human cells behaving unusually4. A cluster of actin filaments was found to appear early during mitosis and then to revolve in cycles through the cytoplasm at a constant angular speed — time-lapse movies of cells with fluorescent filaments revealed circling waves (Fig. 1) that looked like a radar display4. Although extremely visually striking, the function of this odd phenomenon had remained a mystery. Moore et al. now shed light on this enigma. Using cutting-edge light-microscopy technology, the authors report evidence that these actin waves have a role in mitochondrial partitioning during mitosis of human cells. Like chromosomal partitioning, mitochondrial inheritance depends on dynamic processes orchestrated by the cytoskeleton — yet it turns out that these partitioning events occur in a completely different way.

Figure 1

Figure 1 | How mitochondrial organelles are distributed during cell division. Moore et al.1 report three types of interaction with filaments of the protein actin that aid the distribution of mitochondria when human cells divide. Using state-of-the-art microscopy, the authors observed that mitochondria can be tethered to cable structures. It has been reported4 previously that some actin filaments in dividing cells form waves that revolve around the cell (black arrow) in a manner reminiscent of a radar display. In these waves, the authors observed two types of interaction between actin and mitochondria. Mitochondria were frequently encased in what looked like a cloud of actin filaments, restricting the organelles’ mobility. Some mitochondria in the waves instead had comet-tail-like structures made of actin filaments, and these organelles moved rapidly (red arrow) in random directions. The authors tracked the fate of labelled mitochondria that were damaged using an experimental technique. The actin-mediated activities helped to mix and divide the mitochondria between the two daughter cells during cell division, resulting in an even distribution of the damaged organelles.

The authors describe three modes of interaction between mitochondria and actin during mitosis (Fig. 1). Previous work5 suggested that the myosin motor protein Myo19 dynamically tethers mitochondria to an actin network and maintains the distribution of mitochondria throughout the cytoplasm. First, Moore and colleagues observed this process in greater detail than had been reported previously, and found that it is independent of the presence of actin waves. Second, within a wave, mitochondria are encased by what looks like clouds of actin filaments that seem to immobilize the organelles. And third, sometimes these clouds ‘opened’, to be followed by an astonishing burst of mitochondrial movement. The organelles were propelled by the rapid growth (polymerization) of actin filaments. This generated what looks like a comet tail made of actin. These mitochondrial movements were rapid, randomly oriented, and covered substantial distances in the cell.

Moore and colleagues’ observation of actin comet tails is particularly exciting. Two decades ago, it was suggested that actin polymerization drives mitochondrial motility in yeast cells6. However, this model is controversial because the transport of mitochondria into the bud that forms when yeast divides is mediated by a myosin motor protein ‘walking’ along actin cables7, and mitochondrial comet tails of actin have not been documented in yeast. Nevertheless, movement that relies on actin dynamics is quite common in animal cells. Such processes contribute to the internalization of vesicles, and actin is hijacked by certain invading microorganisms to enable them to move in the cytoplasm of a host cell.

The authors present stunning images of twin actin tails emanating from the front of mitochondria and extending behind the organelle, similar to the contrails left in the sky by twin-engine aircraft. The comet tails that Moore and colleagues observed were often slightly twisted, and closely resemble the comet tails of actin generated by certain bacteria of the genus Rickettsia that infect cells and cause disease8.

What might be the function of these actin dynamics in mitochondrial inheritance? Mitochondria contain their own genome, which encodes essential proteins required for energy generation through a pathway called the respiratory chain (also known as the electron-transport chain). If there is an accumulation of mitochondria with mutations in the DNA that encodes such components, a cell’s energy production would be compromised. Moreover, if a cell inherits a high load of mitochondria with mutated DNA from its mother cell, each subsequent cell division would pass on these energy defects to the progeny cells. Abnormalities could therefore spread to a large part of the tissue and ultimately impair organ function. This possibility suggests why actin dynamics might actively contribute to the distribution of mitochondria being inherited.

Moore et al. used what are called optogenetic tools to generate cells with damaged mitochondria. The authors triggered the production of damaging reactive oxygen species in a subset of mitochondria and at the same time specifically labelled these mitochondria. They observed that the dispersion of damaged organelles depends on the presence of cycling actin waves. The authors fed their experimental data into computer models, and the results suggest that the actin waves trigger bursts of movement driven by comet tails that randomly distribute mitochondria during cell division. This activity promotes organelle dispersion, and ensures that the burden of damaged mitochondria is evenly split between the two daughter cells of the mitotic division (Fig. 1).

The authors’ discoveries reveal several intriguing aspects worthy of further study. It will be interesting to determine the molecular pathways that regulate actin dynamics on the mitochondrial surface. A previous study9 reported that revolving actin waves regulate the balance between the division and fusion of mitochondria during the interphase stage of the cell cycle, which precedes mitosis. It will be important to discover whether mitochondrial movement, interconnectivity and dispersion are processes that mutually affect each other.

Certain types of cell divide asymmetrically and generate daughter cells with different fates. During the division of a stem cell, the older mitochondria in the dividing cell are preferentially partitioned to the daughter cell that is destined to differentiate, whereas the younger and ‘fitter’ mitochondria are apportioned to the daughter cell that maintains stem-cell properties10. One can predict, therefore, that mitochondria mixing is suppressed in these cells and that other, as yet unknown, mechanisms ensure the asymmetric inheritance of mitochondria. Clearly, mitochondrial research will yield many more surprises in the future.

Nature 591, 535-537 (2021)

References

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    Moore, A. S. et al. Nature 591, 659–664 (2021).

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    Chung, J. Y., Steen, J. A. & Schwarz, T. L. Cell Rep. 16, 2142–2155 (2016).

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    Mitsushima, M. et al. J. Cell Biol. 191, 453–462 (2010).

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    Rohn, J. L. et al. Curr. Biol. 24, 2598–2605 (2014).

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    Boldogh, I. R. et al. Proc. Natl Acad. Sci. USA 98, 3162–3167 (2001).

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    Van Kirk, L. S., Hayes, S. F. & Heinzen, R. A. Infect. Immun. 68, 4706–4713 (2000).

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    Moore, A. S., Wong, Y. C., Simpson, C. L. & Holzbaur, E. L. Nature Commun. 7, 12886, (2016).

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    Katajisto, P. et al. Science 348, 340–343 (2015).

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