Amitosis ('' a-'' + ''mitosis''), also called karyostenosis or direct cell division or binary fission, is cell proliferation that does not occur by

mitosis In cell biology, mitosis () is a part of the cell cycle in which replicated chromosomes are separated into two new nuclei. Cell division by mitosis gives rise to genetically identical cells in which the total number of chromosomes is maintai ...

, the mechanism usually identified as essential for

cell division Cell division is the process by which a parent cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukaryotes, there ...

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...

s. The polyploid macronucleus found in

ciliates The ciliates are a group of alveolates characterized by the presence of hair-like organelles called cilia, which are identical in structure to eukaryotic flagella, but are in general shorter and present in much larger numbers, with a different ...

divides amitotically. While normal mitosis results in a precise division of parental

alleles An allele (, ; ; modern formation from Greek ἄλλος ''állos'', "other") is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution. ::"The chrom ...

, amitosis results in a random distribution of parental alleles. Ploidy levels of >1000 in some species means both parental alleles can be maintained over many generations, while species with fewer numbers of each chromosome will tend to become homozygous for one or the other parental allele through a process known as phenotypic or allelic assortment. It does not involve maximal condensation of chromatin into chromosomes, observable by light microscopy as they line up in pairs along the metaphase plate. It does not involve these paired structures being pulled in opposite directions by a mitotic spindle to form daughter cells. Rather, it effects nuclear proliferation without the involvement of chromosomes, unsettling for cell biologists who have come to rely on the mitotic figure as reassurance that chromatin is being equally distributed into daughter cells. The phenomenon of amitosis, even though it is an accepted as occurring in ciliates, continues to meet with skepticism about its role in mammalian cell proliferation, perhaps because it lacks the reassuring iconography of mitosis. Of course the relatively recent discovery of

copy number variations Copy number variation (CNV) is a phenomenon in which sections of the genome are repeated and the number of repeats in the genome varies between individuals. Copy number variation is a type of structural variation: specifically, it is a type of G ...

(CNVs) in mammalian cells within an organ significantly challenges the age-old assumption that every cell in an organism must inherit an exact copy of the parental genome to be functional. Rather than CNVs resulting from mitosis gone awry, some of this variation may arise from amitosis, and may be both desirable and necessary. Furthermore, ciliates possess a mechanism for adjusting copy numbers of individual genes during amitosis of the macronucleus. Amitosis was first described in 1880 by

Walther Flemming Walther Flemming (21 April 1843 – 4 August 1905) was a German biologist and a founder of cytogenetics. He was born in Sachsenberg (now part of Schwerin) as the fifth child and only son of the psychiatrist Carl Friedrich Flemming (1799–18 ...

(more celebrated for describing mitosis) and others (Child, 1907). For a few years thereafter, it was common for biologists to think cells sometimes divided by mitosis but at other times could divide by amitosis. However, since the turn of the twentieth century, amitosis has not received much attention. Using "mitosis in mammalian cells" as a search term in the Medline data-base calls up more than 10,000 studies dealing with mitosis, whereas "amitosis in mammalian cells" retrieves the titles of fewer than 50 papers. This absence of data has led many scientists to conclude that amitosis does not exist, or is minimally important—if any means of proliferation can be deemed "minimally important" while the war on cancer is not yet won. Accordingly, a resurgence of interest in the role of amitosis in mammalian proliferation has been building over the past two to three decades. A review of the resulting literature not only affirms the involvement of amitosis in cell proliferation, it also explores the existence of more than one amitotic mechanism capable of producing "progeny nuclei" without the involvement of "mitotic chromosomes." One form of amitosis involves fissioning, a nucleus splitting in two without the involvement of chromosomes, and has been reported in placental tissue as well as in cells grown from that tissue in rats, in human trophoblasts, and in mouse trophoblasts. Amitosis by fissioning has also been reported in mammalian liver cells and human adrenal cells. Chen and Wan not only reported amitosis in rat liver, but also presented a mechanism for a four-stage amitotic process whereby chromatin threads are reproduced and equally distributed to daughter cells as the nucleus splits in two. Additional examples of non-mitotic proliferation, and important insights into underlying mechanisms, have resulted from extensive work with

polyploid Polyploidy is a condition in which the cells of an organism have more than one pair of ( homologous) chromosomes. Most species whose cells have nuclei ( eukaryotes) are diploid, meaning they have two sets of chromosomes, where each set conta ...

cells. Such cells, long acknowledged to exist, were once believed simply to be anomalous.
Accumulating research
including in the liver now suggests that cells containing multiple copies of the genome are importantly involved in a cell's ability to adapt to its environment. A couple of decades of research has shown that polyploid cells are frequently "reduced" to diploid cells by amitosis (Zybina et al.). For instance, naturally occurring polyploid placental cells have been shown capable of producing nuclei with diploid or near-diploid complements of DNA. Furthermore, Zybina and her colleagues have demonstrated that such nuclei, derived from polyploid placental cells, receive one or more copies of a microscopically identifiable region of the chromatin, demonstrating that even without the reassuring iconography of identical chromosomes being distributed into "identical" daughter cells, this particular amitotic process results in representative transmission of chromatin. Studying rat polyploid trophoblasts, this research group has shown that the nuclear envelope of the giant nucleus is involved in this subdivision of a highly polyploid nucleus into low-ploidy nuclei. Polyploid cells are also at the heart of experiments to determine how some cells may survive chemotherapy. Erenpreisa and colleagues have shown that following treatment of cultured cells with mitosis-inhibiting chemicals (similar to what is used in some chemotherapy), a small population of induced polyploid cells survives. Eventually this population can give rise to "normal" diploid cells by formation of polyploid chromatin bouquets that return to an interphase state, and separate into several secondary nuclei. Intriguing phenomena including controlled autophagic degradation of some DNA as well as production of nuclear envelope-limited sheets accompanies the process. Since neither of these depolyploidizations involves mitotic chromosomes, they conform to the broad definition of amitosis. There are also multiple reports of amitosis occurring when nuclei bud out through the plasma membrane of a polyploid cell. Such a process has been shown to occur in amniotic cells transformed by a virus as well as in mouse embryo fibroblast lines exposed to carcinogens. A similar process called extrusion has been described for mink trophoblasts, a tissue in which fissioning is also observed.

Asymmetric cell division An asymmetric cell division produces two daughter cells with different cellular fates. This is in contrast to symmetric cell divisions which give rise to daughter cells of equivalent fates. Notably, stem cells divide asymmetrically to give rise to ...

has also been described in polyploid giant cancer cells and low eukaryotic cells and reported to occur by the amitotic processes of splitting, budding, or burst-like mechanisms. Similarly, two different kinds of amitosis have been described in monolayers of Ishikawa endometrial cells
Fleming, 2014
An example of amitosis particularly suited to the formation of multiple differentiated nuclei in a reasonably short period of time has been shown to occur during the differentiation of fluid-enclosing hemispheres called domes from adherent Ishikawa endometrial monolayer cells during an approximately 20-hour period.
Fleming 1995Fleming, 1999
Aggregates of nuclei from monolayer syncytia become enveloped in mitochondrial membranes, forming structures (mitonucleons) that become elevated as a result of vacuole formation during the initial 6 hours of differentiation
Fleming 1998Fleming, 2015a
. Over the next 4 or 5 hours, chromatin from these aggregated nuclei becomes increasingly pycnotic, eventually undergoing

karyolysis Karyolysis (from Greek κάρυον ''karyon—''kernel, seed, or nucleus), and λύσις ''lysis'' from λύειν ''lyein'', "to separate") is the complete dissolution of the chromatin of a dying cell due to the enzymatic degradation by endonuc ...

and

karyorrhexis Karyorrhexis (from Greek κάρυον ''karyon'', "kernel, seed or nucleus", and ῥῆξις ''rhexis'', "bursting") is the destructive fragmentation of the nucleus of a dying cell whereby its chromatin is distributed irregularly throughout the c ...

in the now-elevated predome structures
Fleming, 2015b
. In other systems such changes accompany

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

but not in the differentiating Ishikawa cells, where the processes appear to accompany changes in DNA essential for the newly created differentiated dome cells. Finally, the chromatin filaments emerging from these processes form a mass from which dozens of dome nuclei are amitotically generated
Fleming, 2015c
over a period of approximately 3 hours with the apparent involvement of nuclear envelope-limited sheets. That all of this may be an iceberg tip is suggested by research from Walter Thilly's laboratory. Examination of fetal gut (5 to 7 weeks), colonic adenomas, and adenocarcinomas has revealed nuclei that look like hollow bells encased in tubular syncytia. These structures can divide symmetrically by an amitotic nuclear fission process, forming new "bells". Or they can fission asymmetrically resulting in one of seven other nuclear morphotypes, five of which appear to be specific to development since they are rarely observed in adult organisms. The research that is accumulating about amitosis suggests that such processes are, indeed, involved in the production of the 37 trillion or so cells in humans, perhaps particularly during the fetal and embryonic phases of development when the majority of these cells are produced, perhaps within the complexity of implantation, perhaps when large numbers of cells are being differentiated, and perhaps in cancerous cells. A word of caution: some examples of cell division formerly thought to belong to this "non-mitotic" class, such as the division of some unicellular eukaryotes
may actually occur by the process of "closed mitosis"
different from open or semi-closed mitotic processes, all involving mitotic chromosomes and classified by the fate of the

nuclear envelope The nuclear envelope, also known as the nuclear membrane, is made up of two lipid bilayer membranes that in eukaryotic cells surround the nucleus, which encloses the genetic material. The nuclear envelope consists of two lipid bilayer membr ...

References

Further reading