Homoplasmy

Last updated
The cell in the top left is heteroplasmic as shown by the normal mitochondria in purple and the mitochondria with a mtDNA mutation in red. As this cell divides, the mitochondria replicate and independently assort into the daughter cells. This leads to both positive and negative (cell shown in red) homoplasmy. Homoplasmy.png
The cell in the top left is heteroplasmic as shown by the normal mitochondria in purple and the mitochondria with a mtDNA mutation in red. As this cell divides, the mitochondria replicate and independently assort into the daughter cells. This leads to both positive and negative (cell shown in red) homoplasmy.

Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical. [1] In normal and healthy tissues, all cells are homoplasmic. [2] Homoplasmic mitochondrial DNA copies may be normal or mutated; [1] however, most mutations are heteroplasmic [2] [3] (only occurring in some copies of mitochondrial DNA). It has been discovered, though, that homoplasmic mitochondrial DNA mutations may be found in human tumors. [4]

Contents

The term may also refer to uniformity of plant plastid DNA, whether occurring naturally or otherwise.[ citation needed ]

Inheritance

In almost every species, mitochondrial DNA is maternally inherited. [2] This means that all of the offspring of a female will have identical and homoplasmic mitochondrial DNA. It is very rare for females to pass on heteroplasmic or homoplasmic mutations because of the genetic bottleneck, where only a few out of many mitochondria actually are passed on to offspring. [2]

The mussel Mytilus edulis is an anomaly in terms of mitochondrial DNA inheritance. Unlike almost all animals, this species has biparental inheritance for mitochondrial DNA, meaning that both the male and the female contribute mitochondria to the offspring. This was discovered when researchers realized that most individuals of a Mytilus edulis population were heteroplasmic. [5] Researchers also believe that this could be a by-product of species hybridization. [5]

Mutations

There is evidence of both homoplasmic and heteroplasmic inherited mutations that lead to disease, though heteroplasmic mutations typically are a precursor to homoplasmic disease. [6] [7] Many diseases resulting from mutations in mitochondrial DNA are not inherited but developed as the untranslated region of mitochondrial DNA (mtDNA) is thought to be particularly susceptible to mutation. [8] Many cancer types are the result of mutations in the mtDNA. For example, a specific type of mutation in one specific area of mtDNA was found to be in several different tumor types. [9]

Mitochondria often undergo fission and fusion, which means that different organelles in the same cell can fuse together to become one mitochondria, or can break apart and become two. [10] This process can be used to mitigate the effects of heteroplasmic mutations. Each mitochondria has multiple nucleoids, which consist of several copies of mtDNA, and when mitochondria fuse together, these nucleoids do not exchange DNA; therefore, if two mitochondria that have different DNA fuse together, they will have only two types of nucleoids. This means that fusion can be used to generate complementary nucleoids if a mutation causes one mitochondria to no longer be functional. Additionally, fission can cause one mitochondria with two different nucleoids to become two mitochondria each with only one type of nucleoid. [10] Some researchers believe that this could be a useful tool to treat diseases caused by mutations in mtDNA. [10]

Inherited homoplasmic diseases

Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy (LHON) is the disease in humans that is most frequently associated with homoplasmy. [7] This condition is characterized by the atrophy of retinal ganglion cells, which leads to central blindness and eventually total blindness. [11] Although it is passed down maternally, it is seen more often in young men than in other ages or sexes, which leads researchers to believe that there are many other genetic or environmental factors that contribute to developing the disease. [11] Specifically, researchers have thought that the genetic component outside of the mitochondria would be on the X chromosome; however, in multiple studies, there have been no findings that suggest this. [12] [13] Environmental factors, cigarette smoke in particular, have been shown to affect LHON's penetrance. [11] In one study, cigarette smoke condensate was used to demonstrate the effects of smoking on cells with the LHON mutation. All cells were homoplasmic, but some were from individuals who were afflicted with LHON and some were from individuals who were just carriers. The researchers found that cigarette smoke condensate lowered the amount of mitochondria in the cells, but that carrier individuals were better able to compensate than those from individuals with LHON. [11] Though there is an additive environmental effect, [11] there is more to learn about why certain homoplasmic individuals have the disease and others do not.

Cancer

Some research has shown that an inherited heteroplasmic mutation can cause cancer in older age as cells become homoplasmic. [6] In one study, doctors found that a cancer patient's tumor consisted of only homoplasmic cells with mutant mtDNA and that healthy cells in his body were heteroplasmic for mutant mtDNA. [6] Additionally, researchers found that the patient's siblings had the same heteroplasmic mutation. This indicates that the heteroplasmic mutation was inherited, and over time led to homoplasmic cells that caused cancer. [6]

See also

Notes and references

  1. 1 2 Heteroplasmy vs. Homoplasmy. University of Miami Faculty of Medicine. Accessed 21 October 2012.
  2. 1 2 3 4 Dimauro, Salvatore; Davidzon, Guido (2005). "Mitochondrial DNA and disease". Annals of Medicine. 37 (3): 222–232. doi: 10.1080/07853890510007368 . PMID   16019721. S2CID   11114978.
  3. ↑ Ballana, E.; Govea, N.; de Cid, R.; Garcia, C.; Arribas, C.; Rosell, J.; Estivill, X. (2008). "Detection of unrecognized low-level mtDNA heteroplasmy may explain the variable phenotypic expressivity of apparently homoplasmic mtDNA mutations". Hum. Mutat. 29 (2): 248–257. doi: 10.1002/humu.20639 . PMID   17999439. S2CID   25493822.
  4. ↑ Coller, HA; Khrapko, K; Bodyak, ND; Nekhaeva, E; Herrero-Jimenez, P; Thilly, WG (2001). "High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection". Nature Genetics. 28 (2): 147–50. doi:10.1038/88859. PMID   11381261. S2CID   11929018.
  5. 1 2 Hoeh, Walter R.; Blakley, Karen H.; Brown, Wesley M. (1 January 1991). "Heteroplasmy Suggests Limited Biparental Inheritance of Mytilus Mitochondrial DNA". Science. 251 (5000): 1488–1490. Bibcode:1991Sci...251.1488H. doi:10.1126/science.1672472. JSTOR   2875830. PMID   1672472.
  6. 1 2 3 4 Gasparre, Giuseppe; Iommarini, Luisa; Porcelli, Anna Maria; Lang, Martin; Ferri, Gian Gaetano; Kurelac, Ivana; Zuntini, Roberta; Mariani, Elisa; Pennisi, Lucia Fiammetta (1 March 2009). "An inherited mitochondrial DNA disruptive mutation shifts to homoplasmy in oncocytic tumor cells". Human Mutation. 30 (3): 391–396. doi: 10.1002/humu.20870 . ISSN   1098-1004. PMID   19086058. S2CID   33063313.
  7. 1 2 Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K. (1988). "Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy". Science. 242 (4884): 1427–1430. Bibcode:1988Sci...242.1427W. doi:10.1126/science.3201231. JSTOR   1702331. PMID   3201231.
  8. ↑ Lightowlers, Robert N.; Chinnery, Patrick F.; Turnbull, Douglass M.; Howell, Neil (1997). "Mammalian mitochondrial genetics: heredity, heteroplasmy and disease" (PDF). Trends in Genetics. 13 (11): 450–455. doi:10.1016/S0168-9525(97)01266-3. PMID   9385842 . Retrieved 8 February 2016.
  9. ↑ Gasparre, Giuseppe; Porcelli, Anna Maria; Bonora, Elena; Pennisi, Lucia Fiammetta; Toller, Matteo; Iommarini, Luisa; Ghelli, Anna; Moretti, Massimo; Betts, Christine M. (22 May 2007). "Disruptive mitochondrial DNA mutations in complex I subunits are markers of oncocytic phenotype in thyroid tumors". Proceedings of the National Academy of Sciences. 104 (21): 9001–9006. Bibcode:2007PNAS..104.9001G. doi: 10.1073/pnas.0703056104 . ISSN   0027-8424. PMC   1885617 . PMID   17517629.
  10. 1 2 3 Gilkerson, Robert W.; Schon, Eric A.; Hernandez, Evelyn; Davidson, Mercy M. (30 June 2008). "Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation". The Journal of Cell Biology. 181 (7): 1117–1128. doi:10.1083/jcb.200712101. ISSN   0021-9525. PMC   2442202 . PMID   18573913.
  11. 1 2 3 4 5 Giordano (2015). "Cigarette toxicity triggers Leber's hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways". Cell Death and Disease. 6 (12): e2021. doi:10.1038/cddis.2015.364. PMC   4720897 . PMID   26673666.
  12. ↑ Pegoraro, Elena; Vettori, Andrea; Valentino, Maria L.; Molon, Annamaria; Mostacciuolo, Maria L.; Howell, Neil; Carelli, Valerio (15 May 2003). "X-inactivation pattern in multiple tissues from two leber's hereditary optic neuropathy (LHON) patients". American Journal of Medical Genetics Part A. 119A (1): 37–40. doi:10.1002/ajmg.a.10211. ISSN   1552-4833. PMID   12707956. S2CID   19349243.
  13. ↑ Handoko, H. Y.; Wirapati, P. J.; Sudoyo, H. A.; Sitepu, M.; Marzuki, S. (1 August 1998). "Meiotic breakpoint mapping of a proposed X linked visual loss susceptibility locus in Leber's hereditary optic neuropathy". Journal of Medical Genetics. 35 (8): 668–671. doi:10.1136/jmg.35.8.668. ISSN   1468-6244. PMC   1051394 . PMID   9719375.

Related Research Articles

<span class="mw-page-title-main">Mitochondrial disease</span> Spontaneously occurring or inherited disorder that involves mitochondrial dysfunction

Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of food molecules into the ATP that powers most cell functions.

Heteroplasmy is the presence of more than one type of organellar genome within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected.

<span class="mw-page-title-main">Leber's hereditary optic neuropathy</span> Mitochondrially inherited degeneration of retinal cells in human

Leber's hereditary optic neuropathy (LHON) is a mitochondrially inherited degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; it predominantly affects young adult males. LHON is transmitted only through the mother, as it is primarily due to mutations in the mitochondrial genome, and only the egg contributes mitochondria to the embryo. Men cannot pass on the disease to their offspring. LHON is usually due to one of three pathogenic mitochondrial DNA (mtDNA) point mutations. These mutations are at nucleotide positions 11778 G to A, 3460 G to A and 14484 T to C, respectively in the ND4, ND1 and ND6 subunit genes of complex I of the oxidative phosphorylation chain in mitochondria.

<span class="mw-page-title-main">MELAS syndrome</span> Medical condition

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the family of mitochondrial diseases, which also include MIDD, MERRF syndrome, and Leber's hereditary optic neuropathy. It was first characterized under this name in 1984. A feature of these diseases is that they are caused by defects in the mitochondrial genome which is inherited purely from the female parent. The most common MELAS mutation is mitochondrial mutation, mtDNA, referred to as m.3243A>G.

Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. [1].

Allotopic expression (AE) refers to expression of genes in the cell nucleus that normally are expressed only from the mitochondrial genome. Biomedically engineered AE has been suggested as a possible future tool in gene therapy of certain mitochondria-related diseases, however this view is controversial. While this type of expression has been successfully carried out in yeast, the results in mammals have been conflicting.

Protofection is a protein-mediated transfection of foreign mitochondrial DNA (mtDNA) into the mitochondria of cells in a tissue to supplement or replace the native mitochondrial DNA already present. The complete mtDNA genome or just fragments of mtDNA generated by polymerase chain reaction can be transferred into the target mitochondria through the technique.

<span class="mw-page-title-main">MT-ND6</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND6 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 6 protein (ND6). The ND6 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the human MT-ND6 gene are associated with Leigh's syndrome, Leber's hereditary optic neuropathy (LHON) and dystonia.

<span class="mw-page-title-main">MT-ND4</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4 (ND4) protein. The ND4 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in the MT-ND4 gene are associated with age-related macular degeneration (AMD), Leber's hereditary optic neuropathy (LHON), mesial temporal lobe epilepsy (MTLE) and cystic fibrosis.

<span class="mw-page-title-main">MT-ND2</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND2 is a gene of the mitochondrial genome coding for the NADH dehydrogenase 2 (ND2) protein. The ND2 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of human MT-ND2 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">MT-ND4L</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND4L is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 4L (ND4L) protein. The ND4L protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of human MT-ND4L are associated with increased BMI in adults and Leber's Hereditary Optic Neuropathy (LHON).

<span class="mw-page-title-main">MT-ATP6</span> Mitochondrial protein-coding gene whose product is involved in ATP synthesis

MT-ATP6 is a mitochondrial gene with the full name 'mitochondrially encoded ATP synthase membrane subunit 6' that encodes the ATP synthase Fo subunit 6. This subunit belongs to the Fo complex of the large, transmembrane F-type ATP synthase. This enzyme, which is also known as complex V, is responsible for the final step of oxidative phosphorylation in the electron transport chain. Specifically, one segment of ATP synthase allows positively charged ions, called protons, to flow across a specialized membrane inside mitochondria. Another segment of the enzyme uses the energy created by this proton flow to convert a molecule called adenosine diphosphate (ADP) to ATP. Mutations in the MT-ATP6 gene have been found in approximately 10 to 20 percent of people with Leigh syndrome.

<span class="mw-page-title-main">MT-ND5</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND5 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 5 protein (ND5). The ND5 protein is a subunit of NADH dehydrogenase (ubiquinone), which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variations in human MT-ND5 are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) as well as some symptoms of Leigh's syndrome and Leber's hereditary optic neuropathy (LHON).

<span class="mw-page-title-main">MT-ND1</span> Mitochondrial gene coding for a protein involved in the respiratory chain

MT-ND1 is a gene of the mitochondrial genome coding for the NADH-ubiquinone oxidoreductase chain 1 (ND1) protein. The ND1 protein is a subunit of NADH dehydrogenase, which is located in the mitochondrial inner membrane and is the largest of the five complexes of the electron transport chain. Variants of the human MT-ND1 gene are associated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh's syndrome (LS), Leber's hereditary optic neuropathy (LHON) and increases in adult BMI.

<span class="mw-page-title-main">Cytochrome c oxidase subunit I</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase I (COX1) also known as mitochondrially encoded cytochrome c oxidase I (MT-CO1) is a protein that is encoded by the MT-CO1 gene in eukaryotes. The gene is also called COX1, CO1, or COI. Cytochrome c oxidase I is the main subunit of the cytochrome c oxidase complex. In humans, mutations in MT-CO1 have been associated with Leber's hereditary optic neuropathy (LHON), acquired idiopathic sideroblastic anemia, Complex IV deficiency, colorectal cancer, sensorineural deafness, and recurrent myoglobinuria.

<span class="mw-page-title-main">Cytochrome c oxidase subunit III</span> Enzyme of the respiratory chain encoded by the mitochondrial genome

Cytochrome c oxidase subunit III (COX3) is an enzyme that in humans is encoded by the MT-CO3 gene. It is one of main transmembrane subunits of cytochrome c oxidase. It is also one of the three mitochondrial DNA (mtDNA) encoded subunits of respiratory complex IV. Variants of it have been associated with isolated myopathy, severe encephalomyopathy, Leber hereditary optic neuropathy, mitochondrial complex IV deficiency, and recurrent myoglobinuria.

Mitohondrial optic neuropathies are a heterogenous group of disorders that present with visual disturbances resultant from mitochondrial dysfunction within the anatomy of the Retinal Ganglion Cells (RGC), optic nerve, optic chiasm, and optic tract. These disturbances are multifactorial, their aetiology consisting of metabolic and/or structural damage as a consequence of genetic mutations, environmental stressors, or both. The three most common neuro-ophthalmic abnormalities seen in mitochondrial disorders are bilateral optic neuropathy, ophthalmoplegia with ptosis, and pigmentary retinopathy.

<span class="mw-page-title-main">Mother's curse</span>

In biology, mother's curse is an evolutionary effect that males inherit deleterious mitochondrial genome (mtDNA) mutations from their mother, while those mutations are beneficial, neutral or less deleterious to females.

Professor Patrick Francis Chinnery, FRCP, FRCPath, FMedSci, is a neurologist, clinician scientist, and Wellcome Trust Principal Research Fellow based in the Medical Research Council Mitochondrial Biology Unit and the University of Cambridge, where he is also Professor of Neurology and Head of the Department of Clinical Neurosciences.

<span class="mw-page-title-main">Alfredo Sadun</span> American ophthalmologist

Alfredo Arrigo Sadun is an American ophthalmologist, academic, author and researcher. He holds the Flora L. Thornton Endowed Chair at Doheny Eye Centers-UCLA and is Vice-Chair of Ophthalmology at UCLA.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.