Content deleted Content added
Edderiofer (talk | contribs) Added citation-needed template |
True, but irrelevant: this does not permanently affect the expression or production of mitochondrial proteins |
||
| (39 intermediate revisions by 19 users not shown) | |||
Line 2:
{{more citations needed|date=February 2014}}
{{Infobox medical condition (new)
| name
| synonyms = Mitochondrial
| image
| caption
| pronounce =
| field
| symptoms =
| complications =
| onset =
| duration =
| types =
| causes =
| risks =
| diagnosis =
| differential =
| prevention =
| treatment =
| medication =
| prognosis =
| frequency =
| deaths =
}}
'''Mitochondrial disease''' is a group of disorders caused by '''mitochondrial dysfunction'''. [[Mitochondria]] are the [[organelle]]s 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 [[adenosine triphosphate|ATP]] that powers most cell functions.
Line 29 ⟶ 30:
== Types ==
{{
Mitochondrial disease can manifest in many different ways<ref>{{Cite web |title=Mitochondrial Diseases |url=https://medlineplus.gov/mitochondrialdiseases.html |access-date=2023-03-15 |website=medlineplus.gov}}</ref> whether in children<ref name=Rahman2020>{{cite journal |vauthors=Rahman S |title=Mitochondrial disease in children |journal=Journal of Internal Medicine |volume=287 |issue=6 |pages=609–633 |date=2020 |pmid=32176382 |doi=10.1111/joim.13054 |url=|doi-access=free }}</ref> or adults.<ref name=LaMorgia2020>{{cite journal |vauthors=La Morgia C, Maresca A, Caporali L, Valentino ML, Carelli V |title=Mitochondrial diseases in adults |journal=Journal of Internal Medicine |volume=287 |issue=6 |pages=592–608 |date=2020 |pmid=32463135 |doi=10.1111/joim.13064 |url=|doi-access=free }}</ref> Examples of mitochondrial diseases include:
* [[Mitochondrial myopathy]]<ref name=Rahman2020/><ref name=LaMorgia2020/>
* Maternally inherited [[diabetes mellitus and deafness]] (MIDD)<ref name=Tsang2018>{{cite book |vauthors=Tsang SH, Aycinena AR, Sharma T |title=Atlas of Inherited Retinal Diseases |chapter=Mitochondrial disorder: maternally inherited diabetes and deafness |series=Advances in Experimental Medicine and Biology |volume=1085 |pages=163–165 |date=2018 |pmid=30578504 |doi=10.1007/978-3-319-95046-4_31 |isbn=978-3-319-95045-7 |chapter-url=}}</ref>
**
* [[Leber's hereditary optic neuropathy]] (LHON)<ref name=LaMorgia2020/>▼
**LHON is an eye disorder characterized by progressive loss of central vision due to degeneration of the optic nerves and retina (apparently affecting between 1 in 30,000 and 1 in 50,000 people<ref name=Shamsnajafabadi2023>{{cite journal |vauthors=Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J |title=Current and future landscape in genetic therapies for Leber hereditary optic neuropathy |journal=Cells |volume=12 |issue=15 |date=2023 |page=2013 |pmid=37566092 |pmc=10416882 |doi=10.3390/cells12152013 |doi-access=free }}</ref>); visual loss typically begins in young adulthood<ref name=Rahman2020/>
▲* [[Leber's hereditary optic neuropathy]] (LHON)
* [[Leigh syndrome]], subacute necrotizing encephalomyelopathy<ref name=Rahman2020a>{{cite book |vauthors=Rahman S |title=Mitochondrial Diseases |chapter=Leigh syndrome |series=Handbook of Clinical Neurology |volume=194 |pages=43–63 |date=2023 |pmid=36813320 |doi=10.1016/B978-0-12-821751-1.00015-4 |isbn=9780128217511 |chapter-url=}}</ref>
** after normal development the disease usually begins late in the first year of life, although onset may occur in adulthood
** a rapid decline in function occurs and is marked by seizures, altered states of consciousness, dementia, ventilatory failure
Line 55 ⟶ 53:
** lactic acidosis
** exercise intolerance
* [[MELAS syndrome]], mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
* [[Mitochondrial DNA depletion syndrome]]
Line 66 ⟶ 64:
* [[Huntington's disease]]
* [[cancer]]
* [[Alzheimer's disease]],<ref>{{cite journal |doi=10.1080/14789450.2021.1918550 |pmid=33874826 |title=Mitochondrial dysfunction in Alzheimer's disease - a proteomics perspective |journal=Expert Review of Proteomics |volume=18 |issue=4 |pages=295–304 |year=2021 |last1=Abyadeh |first1=Morteza |last2=Gupta |first2=Vivek|last3=Chitranshi|first3=Nitin|last4=Gupta|first4=Veer|last5=Wu|first5=Yunqi|last6=Saks|first6=Danit|last7=WanderWall|first7=Roshana|last8=Fitzhenry|first8=Matthew J|last9=Basavarajappa|first9=Devaraj |last10=You|first10=Yuyi|last11=H Hosseini|first11=Ghasem|last12=A Haynes|first12=Paul|last13= L Graham |first13=Stuart|last14=Mirzaei|first14=Mehdi |s2cid=233310698 }}</ref>
* [[Parkinson's disease]]
* [[bipolar disorder]],<ref>{{cite journal |doi=10.1038/sj.mp.4001711 |pmid=16027739 |title=Mitochondrial dysfunction in bipolar disorder: Evidence from magnetic resonance spectroscopy research |journal=Molecular Psychiatry |volume=10 |issue=10 |pages=900–19 |year=2005 |last1=Stork |first1=C |last2=Renshaw |first2=P F |doi-access=free }}</ref><ref name="ReferenceA">{{cite journal |doi=10.1016/j.yexmp.2006.09.008 |pmid=17239370 |title=Mitochondrial dysfunction and molecular pathways of disease |journal=Experimental and Molecular Pathology |volume=83 |issue=1 |pages=84–92 |year=2007 |last1=Pieczenik |first1=Steve R |last2=Neustadt |first2=John }}</ref><ref>{{cite journal |doi=10.1177/0004867412449303 |pmid=22711881 |title=Mitochondrial modulators for bipolar disorder: A pathophysiologically informed paradigm for new drug development |journal=Australian & New Zealand Journal of Psychiatry |volume=47 |issue=1 |pages=26–42 |year=2012 |last1=Nierenberg |first1=Andrew A |last2=Kansky |first2=Christine |last3=Brennan |first3=Brian P |last4=Shelton |first4=Richard C |last5=Perlis |first5=Roy |last6=Iosifescu |first6=Dan V |s2cid=22983555 }}</ref> [[schizophrenia]], aging and senescence,<ref>{{cite journal | doi=10.1016/j.ebiom.2022.103815 |pmid=35085849 |title=Comprehensive summary of mitochondrial DNA alterations in the postmortem human brain: A systematic review|journal=eBioMedicine|volume=76|issue=103815|year=2022|last1=Valiente-Pallejà|first1=A|last2=Tortajada |first2=J |last3=Bulduk|first3=BK|page=103815 |pmc=8790490 |doi-access=free}}</ref> anxiety disorders<ref>{{cite journal |last1=Misiewicz |first1=Zuzanna |last2=Iurato |first2=Stella |last3=Kulesskaya |first3=Natalia |last4=Salminen |first4=Laura |last5=Rodrigues |first5=Luis |last6=Maccarrone |first6=Giuseppina |last7=Martins |first7=Jade |last8=Czamara |first8=Darina |last9=Laine |first9=Mikaela A. |last10=Sokolowska |first10=Ewa |last11=Trontti |first11=Kalevi |last12=Rewerts |first12=Christiane |last13=
* [[cardiovascular disease]]
* [[sarcopenia]]
* [[chronic fatigue syndrome]]<ref name="ReferenceA"/>
* [[ALS]]<ref>{{cite journal |last1=Muyderman |first1=H |last2=Chen |first2=T |title=Mitochondrial dysfunction in amyotrophic lateral sclerosis – a valid pharmacological target? |journal=British Journal of Pharmacology |date=April 2014 |volume=171 |issue=8 |pages=2191–2205 |doi=10.1111/bph.12476 |pmid=24148000 |pmc=3976630 }}</ref>
The body, and each mutation, is modulated by other genome variants; the mutation that in one individual may cause liver disease might in another person cause a brain disorder. The severity of the specific defect may also be great or small. Some defects include [[exercise intolerance]]. Defects often affect the operation of the mitochondria and multiple tissues more severely, leading to multi-system diseases.<ref name="pmid22424226">{{cite journal |vauthors = Nunnari J, Suomalainen A |title = Mitochondria: in sickness and in health |journal = Cell |volume = 148 |issue = 6 |pages = 1145–59 |year = 2012 |pmid = 22424226 |pmc = 5381524 |doi = 10.1016/j.cell.2012.02.035 }}</ref>
It has also been reported that drug tolerant cancer cells have an increased number and size of mitochondria, which suggested an increase in mitochondrial biogenesis.
As a rule, mitochondrial diseases are worse when the defective mitochondria are present in the [[muscle]]s, [[cerebrum]], or [[nerve]]s,<ref name=pmid17637511>{{cite journal |doi=10.1159/000105676 |pmid=17637511 |title=Hematological Manifestations of Primary Mitochondrial Disorders |journal=Acta Haematologica |volume=118 |issue=2 |pages=88–98 |year=2007 |last1=Finsterer |first1=Josef |s2cid=24222021 }}</ref> because these cells use more energy than most other cells in the body.
Line 86 ⟶ 85:
==Causes==
Mitochondrial disorders may be caused by [[mutations]] (acquired or inherited), in [[mitochondrial DNA]] (mtDNA), or in [[nuclear gene]]s that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of [[drugs]], [[infections]], or other environmental causes.<ref>{{Cite web|url=https://meshb.nlm.nih.gov/record/ui?ui=D028361|title=Mitochondrial diseases|website=MeSH|access-date=2 August 2019
[[File:Maternal Inheritance - mitochondrial DNA.png|thumb|Example of a pedigree for a genetic trait inherited by mitochondrial DNA in animals and humans. Offspring of the males with the trait don't inherit the trait. Offspring of the females with the trait always inherit the trait (independently from their own gender).]]
Line 93 ⟶ 92:
Mitochondria possess many of the same DNA repair pathways as nuclei do—but not all of them;<ref>{{cite journal | vauthors = Alexeyev M, Shokolenko I, Wilson G, LeDoux S | title = The maintenance of mitochondrial DNA integrity--critical analysis and update | journal = Cold Spring Harbor Perspectives in Biology | volume = 5 | issue = 5 | pages = a012641 | date = May 2013 | pmid = 23637283 | pmc = 3632056 | doi = 10.1101/cshperspect.a012641 }}</ref> therefore, mutations occur more frequently in mitochondrial DNA than in nuclear DNA (see [[Mutation rate]]). This means that mitochondrial DNA disorders may occur spontaneously and relatively often. Defects in enzymes that control mitochondrial [[DNA replication]] (all of which are encoded for by genes in the nuclear DNA) may also cause mitochondrial DNA mutations.
Most mitochondrial function and biogenesis is controlled by [[nuclear DNA]]. Human mitochondrial DNA encodes 13 proteins of the [[respiratory chain]], while most of the estimated 1,500 proteins and components targeted to mitochondria are nuclear-encoded. Defects in nuclear-encoded mitochondrial genes are associated with hundreds of clinical disease phenotypes including [[anemia]], [[dementia]], [[hypertension]], [[lymphoma]], [[retinopathy]], [[seizures]], and [[neurodevelopmental disorders]].<ref>{{cite journal |author2-link=Helen H. Lu |vauthors = Scharfe C, Lu HH, Neuenburg JK, Allen EA, Li GC, Klopstock T, Cowan TM, Enns GM, Davis RW |title = Mapping gene associations in human mitochondria using clinical disease phenotypes |journal = PLOS Comput Biol |year = 2009 |pmid = 19390613 |volume = 5 |issue = 4 |pages = e1000374 |doi = 10.1371/journal.pcbi.1000374 |pmc = 2668170 |veditors = Rzhetsky A|bibcode = 2009PLSCB...5E0374S |doi-access = free }}</ref>
A study by Yale University researchers (published in the February 12, 2004, issue of the ''[[New England Journal of Medicine]]'') explored the role of mitochondria in insulin resistance among the offspring of patients with type 2 diabetes.<ref name="Petersen et al.">{{cite journal |last1=Petersen |first1=Kitt Falk |last2=Dufour |first2=Sylvie |last3=Befroy |first3=Douglas |last4=Garcia |first4=Rina |last5=Shulman |first5=Gerald I. |title=Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes |journal=New England Journal of Medicine |date=12 February 2004 |volume=350 |issue=7
Other studies have shown that the mechanism may involve the interruption of the mitochondrial signaling process in body cells ([[intramyocellular lipids]]). A study conducted at the Pennington Biomedical Research Center in Baton Rouge, Louisiana<ref>
==Mechanisms==
The effective overall energy unit for the available body energy is referred to as the daily [[glycogen]] generation capacity,<ref name=Chemiosomosis >{{cite web|last=Mitchell|first=Peter|title=David Keilin's respiratory chain concept and its chemiosmotic consequences|url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/1978/mitchell-lecture.pdf|publisher=Nobel institute}}</ref><ref name=Dichloroacetate >{{cite journal|last=Michelakis|first=Evangelos|title=A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth|journal=University of Alberta|publisher=University of Alberta, 2007|doi=10.1016/j.ccr.2006.10.020|volume=11|issue=1|pages=37–51|pmid=17222789|date=January 2007|doi-access=free}}</ref><ref name="Lorini & Ciman" >{{cite journal|last=Lorini & Ciman|first=M, & M|title=Hypoglycaemic action of Diisopropylammonium salts in experimental diabetes|journal=Institute of Biochemistry, University of Padua, September 1962|publisher=Biochemical Pharmacology|doi=10.1016/0006-2952(62)90177-6|volume=11|issue=9|pages=823–827|year=1962|pmid=14466716}}</ref> and is used to compare the mitochondrial output of
The glycogen generation capacity is entirely dependent on, and determined by, the operating levels of the [[mitochondria]] in all of the [[Cell (biology)|cells]] of the [[human body]];<ref name="Dichloroacetate pharmacology" >{{cite journal |vauthors = Stacpoole PW, Henderson GN, Yan Z, James MO |title = Clinical pharmacology and toxicology of dichloroacetate |journal = Environ. Health Perspect. |volume = 106
== Diagnosis ==
Mitochondrial diseases are usually detected by analysing muscle samples, where the presence of these organelles is higher. The most common tests for the detection of these diseases are:
# [[Southern blot]] to detect
# [[Polymerase chain reaction]] and specific [[mutation testing]]<ref>{{cite journal |last1=Bulduk |first1=Bengisu Kevser |last2=Kiliç |first2=Hasan Basri |last3=Bekircan-Kurt |first3=Can Ebru |last4=Haliloğlu |first4=Göknur |last5=Erdem Özdamar |first5=Sevim |last6=Topaloğlu |first6=Haluk |last7=Kocaefe |first7=Y. Çetin |title=A Novel Amplification-Refractory Mutation System-PCR Strategy to Screen MT-TL1 Pathogenic Variants in Patient Repositories |journal=Genetic Testing and Molecular Biomarkers |date=March 2020 |volume=24 |issue=3 |pages=165–170 |doi=10.1089/gtmb.2019.0079 |pmid=32167396 |s2cid=212693790 }}</ref>
# [[Sequencing]]
==Treatments==
Although research is ongoing, treatment options are currently limited; [[vitamin]]s are frequently prescribed, though the evidence for their effectiveness is limited.<ref>{{cite journal |vauthors=Marriage B, Clandinin MT, Glerum DM |title=Nutritional cofactor treatment in mitochondrial disorders |journal=J Am Diet Assoc |volume=103 |issue=8 |pages=1029–38 |year=2003 |pmid=12891154 |doi=10.1016/S0002-8223(03)00476-0}}</ref>
[[Pyruvate]] has been proposed in 2007 as a treatment option.<ref>{{cite journal |vauthors=Tanaka M, Nishigaki Y, Fuku N, Ibi T, Sahashi K, Koga Y |title=Therapeutic potential of pyruvate therapy for mitochondrial diseases |journal=Mitochondrion |volume=7 |issue=6 |pages=399–401 |year=2007 |pmid= 17881297 |doi=10.1016/j.mito.2007.07.002}}</ref> [[N-acetyl cysteine]] reverses many models of mitochondrial dysfunction.<ref>{{cite journal | author = Frantz MC, Wipf P | date = Jun 2010 | title = Mitochondria as a target in treatment | journal = Environ Mol Mutagen | volume = 51 | issue = 5| pages = 462–75 | doi = 10.1002/em.20554 | pmid = 20175113 | pmc = 2920596 | bibcode = 2010EnvMM..51..462F }}</ref> In the case of mood disorders, specifically [[bipolar disorder]], it is hypothesized that N-acetyl-cysteine (NAC), acetyl-L-carnitine (ALCAR), S-adenosylmethionine (SAMe), coenzyme Q10 (CoQ10), alpha-lipoic acid (ALA), creatine monohydrate (CM), and melatonin could be potential treatment options.<ref>{{cite journal |vauthors=Nierenberg, Andrew A, Kansky, Christine, Brennan, Brian P, Shelton, Richard C, Perlis, Roy, Iosifescu, Dan V |title=Mitochondrial modulators for bipolar disorder: A pathophysiologically informed paradigm for new drug development |journal=Australian & New Zealand Journal of Psychiatry |volume=47 |issue=1 |pages=26–42 |year=2012 |doi=10.1177/0004867412449303|pmid=22711881 |s2cid=22983555 }}</ref>
===Gene therapy prior to conception===
[[Mitochondrial replacement therapy]] (MRT)
In September 2012 a public consultation was launched in the UK to explore the ethical issues involved.<ref>{{cite news|title=Regulator to consult public over plans for new fertility treatments|url=https://www.theguardian.com/science/2012/sep/17/genetics-embryo-dna-mitochondrial-disease|access-date=8 October 2012|newspaper=The Guardian|date=2012-09-17|location=London|first=Ian|last=Sample}}</ref> Human genetic engineering was used on a small scale to allow infertile women with genetic defects in their [[mitochondria]] to have children.<ref name="bbc">
Line 123 ⟶ 122:
[[Embryo]]nic mitochondrial transplant and [[protofection]] have been proposed as a possible treatment for inherited mitochondrial disease, and [[allotopic expression]] of mitochondrial proteins as a radical treatment for mtDNA mutation load.
In June 2018 Australian Senate's Senate Community Affairs References Committee recommended a move towards legalising [[Mitochondrial replacement therapy]] (MRT). Research and clinical applications of MRT were overseen by laws made by federal and state governments. State laws were, for the most part, consistent with federal law. In all states, legislation prohibited the use of MRT techniques in the clinic, and except for Western Australia, research on a limited range of MRT was permissible up to day 14 of embryo development, subject to a license being granted. In 2010, the Hon. Mark Butler MP, then Federal Minister for Mental Health and Ageing, had appointed an independent committee to review the two relevant acts: the ''Prohibition of Human Cloning for Reproduction Act 2002'' and the ''Research Involving Human Embryos Act 2002''. The
Currently, human clinical trials are underway at GenSight Biologics (ClinicalTrials.gov # NCT02064569) and the University of Miami (ClinicalTrials.gov # NCT02161380) to examine the safety and efficacy of mitochondrial gene therapy in Leber's hereditary optic neuropathy.
Line 130 ⟶ 129:
About 1 in 4,000 children in the United States will develop mitochondrial disease by the age of 10 years. Up to 4,000 children per year in the US are born with a type of mitochondrial disease.<ref>[http://biochemgen.ucsd.edu/mmdc/brochure.htm The Mitochondrial and Metabolic Disease Center<!-- Bot generated title -->]</ref> Because mitochondrial disorders contain many variations and subsets, some particular mitochondrial disorders are very rare.
The average number of births per year among women at risk for transmitting mtDNA disease is estimated to approximately 150 in the [[United Kingdom]] and 800 in the [[United States]].<ref name="GormanGrady2015">{{cite journal |last1=Gorman |first1=Gráinne S. |last2=Grady |first2=John P. |last3=Ng |first3=Yi |last4=Schaefer |first4=Andrew M. |last5=McNally |first5=Richard J. |last6=Chinnery |first6=Patrick F. |last7=Yu-Wai-Man |first7=Patrick |last8=Herbert |first8=Mary |last9=Taylor |first9=Robert W. |last10=McFarland |first10=Robert |last11=Turnbull |first11=Doug M.
==History==
The first pathogenic mutation in mitochondrial DNA was identified in 1988; from that time to 2016, around 275 other disease-causing mutations were identified.<ref name=NAS2016ethics>{{cite book |
==Notable cases==
Notable people
* [[Mattie Stepanek]], a poet, peace advocate, and motivational speaker who
* [[Rocco Baldelli]], a coach and former center fielder in [[Major League Baseball]] who had to retire from active play at age 29 due to mitochondrial channelopathy.
* [[Charlie Gard case|Charlie Gard]], a British boy who
* [[Charles Darwin]], a nineteenth century naturalist who suffered from a disabling illness, is speculated to have [[MELAS syndrome]].<ref>{{cite journal |last1=Hayman |first1=John |title=Charles Darwin's Mitochondria |journal=Genetics |date=May 2013 |volume=194 |issue=1 |pages=21–25 |doi=10.1534/genetics.113.151241 |pmid=23633139 |pmc=3632469 }}</ref>
==References==
Line 145:
== External links ==
{{Commons category|Mitochondrial diseases}}▼
{{Mitochondrial diseases}}
* {{Curlie|Health/Conditions_and_Diseases/Neurological_Disorders/Brain_Diseases/Metabolic/Mitochondrial/}}▼
* [http://www.mitopatients.org International Mito Patients (IMP)]▼
{{Medical resources
| DiseasesDB = 28840
Line 152 ⟶ 156:
| SNOMED CT = 240096000
}}
{{Authority control}}
▲{{Commons category|Mitochondrial diseases}}
▲* {{Curlie|Health/Conditions_and_Diseases/Neurological_Disorders/Brain_Diseases/Metabolic/Mitochondrial/}}
▲* [http://www.mitopatients.org International Mito Patients (IMP)]
[[Category:Mitochondrial diseases| ]]
| |||