Editing Mitochondrion (section)

==Dysfunction and disease==

===Mitochondrial diseases===
{{Main|Mitochondrial disease}}

Damage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to their influence in cell metabolism. Mitochondrial disorders often present as neurological disorders, including [[autism]].<ref name="Griffiths-2017" /> They can also manifest as [[myopathy]], [[diabetes]], multiple [[endocrinopathy]], and a variety of other systemic disorders.<ref name="Zeviani-2004">{{cite journal | vauthors = Zeviani M, Di Donato S | title = Mitochondrial disorders | journal = Brain | volume = 127 | issue = Pt 10 | pages = 2153–2172 | date = October 2004 | pmid = 15358637 | doi = 10.1093/brain/awh259 | doi-access = free }}</ref> Diseases caused by mutation in the mtDNA include [[Kearns–Sayre syndrome]], [[MELAS syndrome]] and [[Leber's hereditary optic neuropathy]].<ref name="Taylor-2005">{{cite journal | vauthors = Taylor RW, Turnbull DM | title = Mitochondrial DNA mutations in human disease | journal = Nature Reviews. Genetics | volume = 6 | issue = 5 | pages = 389–402 | date = May 2005 | pmid = 15861210 | pmc = 1762815 | doi = 10.1038/nrg1606 }}</ref> In the vast majority of cases, these diseases are transmitted by a female to her children, as the [[zygote]] derives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, [[Pearson syndrome]], and progressive external [[ophthalmoparesis|ophthalmoplegia]] are thought to be due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, [[MERRF syndrome]], and others are due to [[point mutation]]s in mtDNA.<ref name="Zeviani-2004" />

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.<ref name="Goldman-2019">{{cite journal | vauthors = Goldman A, Khiste S, Freinkman E, Dhawan A, Majumder B, Mondal J, Pinkerton AB, Eton E, Medhi R, Chandrasekar V, Rahman MM, Ichimura T, Gopinath KS, Majumder P, Kohandel M, Sengupta S | title = Targeting tumor phenotypic plasticity and metabolic remodeling in adaptive cross-drug tolerance | journal = Science Signaling | volume = 12 | issue = 595 | date = August 2019 | pmid = 31431543 | pmc = 7261372 | doi = 10.1126/scisignal.aas8779 }}</ref> A 2022 study in ''Nature Nanotechnology'' has reported that cancer cells can hijack the mitochondria from immune cells via physical tunneling nanotubes.<ref>{{cite journal | vauthors = Saha T, Dash C, Jayabalan R, Khiste S, Kulkarni A, Kurmi K, Mondal J, Majumder PK, Bardia A, Jang HL, Sengupta S | title = Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells | journal = Nature Nanotechnology | volume = 17 | issue = 1 | pages = 98–106 | date = January 2022 | pmid = 34795441 | pmc = 10071558 | doi = 10.1038/s41565-021-01000-4 | bibcode = 2022NatNa..17...98S }}</ref>

In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in [[Friedreich's ataxia]], [[hereditary spastic paraplegia]], and [[Wilson's disease]].<ref>{{cite journal | vauthors = Chinnery PF, Schon EA | title = Mitochondria | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 74 | issue = 9 | pages = 1188–1199 | date = September 2003 | pmid = 12933917 | pmc = 1738655 | doi = 10.1136/jnnp.74.9.1188 }}</ref> These diseases are inherited in a [[dominance relationship]], as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations of oxidative phosphorylation enzymes, such as [[coenzyme Q10]] deficiency and [[Barth syndrome]].<ref name="Zeviani-2004"/> Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may be a link between [[pesticide]] exposure and the later onset of [[Parkinson's disease]].<ref>{{cite journal | vauthors = Sherer TB, Betarbet R, Greenamyre JT | title = Environment, mitochondria, and Parkinson's disease | journal = The Neuroscientist | volume = 8 | issue = 3 | pages = 192–197 | date = June 2002 | pmid = 12061498 | doi = 10.1177/1073858402008003004 }}</ref><ref>{{cite journal | vauthors = Gomez C, Bandez MJ, Navarro A | title = Pesticides and impairment of mitochondrial function in relation with the parkinsonian syndrome | journal = Frontiers in Bioscience | volume = 12 | pages = 1079–1093 | date = January 2007 | pmid = 17127363 | doi = 10.2741/2128 | doi-access = free }}</ref> Other pathologies with etiology involving mitochondrial dysfunction include [[schizophrenia]], [[bipolar disorder]], [[dementia]], [[Alzheimer's disease]],<ref>{{cite journal | vauthors = Lim YA, Rhein V, Baysang G, Meier F, Poljak A, Raftery MJ, Guilhaus M, Ittner LM, Eckert A, Götz J | title = Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction | journal = Proteomics | volume = 10 | issue = 8 | pages = 1621–1633 | date = April 2010 | pmid = 20186753 | doi = 10.1002/pmic.200900651 }}</ref><ref>{{cite journal | vauthors = King JV, Liang WG, Scherpelz KP, Schilling AB, Meredith SC, Tang WJ | title = Molecular basis of substrate recognition and degradation by human presequence protease | journal = Structure | volume = 22 | issue = 7 | pages = 996–1007 | date = July 2014 | pmid = 24931469 | pmc = 4128088 | doi = 10.1016/j.str.2014.05.003 }}</ref> Parkinson's disease, [[epilepsy]], [[stroke]], [[cardiovascular disease]], [[myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS), [[retinitis pigmentosa]], and [[diabetes mellitus]].<ref>{{cite journal | vauthors = Schapira AH | title = Mitochondrial disease | journal = Lancet | volume = 368 | issue = 9529 | pages = 70–82 | date = July 2006 | pmid = 16815381 | doi = 10.1016/S0140-6736(06)68970-8 }}</ref><ref name="Pieczenik-2007">{{cite journal | vauthors = Pieczenik SR, Neustadt J | title = Mitochondrial dysfunction and molecular pathways of disease | journal = Experimental and Molecular Pathology | volume = 83 | issue = 1 | pages = 84–92 | date = August 2007 | pmid = 17239370 | doi = 10.1016/j.yexmp.2006.09.008 }}</ref>

Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in [[type 2 diabetics]]. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases [[uncoupling proteins]] (UCPs) and potentiate proton leakage through the [[adenine nucleotide translocator]] (ANT), the combination of which [[uncoupler|uncouples]] the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxidation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria are uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. Decreased intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well, causing cardiac problems for diabetics.<ref>{{cite journal | vauthors = Bugger H, Abel ED | title = Mitochondria in the diabetic heart | journal = Cardiovascular Research | volume = 88 | issue = 2 | pages = 229–240 | date = November 2010 | pmid = 20639213 | pmc = 2952534 | doi = 10.1093/cvr/cvq239 }}</ref>

Mitochondria also modulate processes such as testicular somatic cell development, spermatogonial stem cell differentiation, luminal acidification, testosterone production in testes, and more. Thus, dysfunction of mitochondria in spermatozoa can be a cause for infertility.<ref>{{cite journal | vauthors = Podolak A, Woclawek-Potocka I, Lukaszuk K | title = The Role of Mitochondria in Human Fertility and Early Embryo Development: What Can We Learn for Clinical Application of Assessing and Improving Mitochondrial DNA? | journal = Cells | volume = 11 | issue = 5 | pages = 797 | date = February 2022 | pmid = 35269419 | pmc = 8909547 | doi = 10.3390/cells11050797 | doi-access = free }}</ref>

In efforts to combat mitochondrial disease, [[mitochondrial replacement therapy]] (MRT) has been developed. This form of in vitro fertilization uses donor mitochondria, which avoids the transmission of diseases caused by mutations of mitochondrial DNA.<ref>{{cite journal | vauthors = May-Panloup P, Boguenet M, Hachem HE, Bouet PE, Reynier P | title = Embryo and Its Mitochondria | journal = Antioxidants | volume = 10 | issue = 2 | pages = 139 | date = January 2021 | pmid = 33498182 | pmc = 7908991 | doi = 10.3390/antiox10020139 | doi-access = free }}</ref> However, this therapy is still being researched and can introduce genetic modification, as well as safety concerns. These diseases are rare but can be extremely debilitating and progressive diseases, thus posing complex ethical questions for public policy.<ref>{{Citation | veditors = Claiborne A, English R, Kahn J |title=Introduction |date=March 17, 2016 |url=https://www.ncbi.nlm.nih.gov/books/NBK355458/ |work=Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations |access-date=December 5, 2023 |publisher=National Academies Press (US) |language=en|vauthors=((Committee on the Ethical and Social Policy Considerations of Novel Techniques for Prevention of Maternal Transmission of Mitochondrial DNA Diseases; Board on Health Sciences Policy; Institute of Medicine; National Academies of Sciences, Engineering, and Medicine))}}</ref>

===Relationships to aging===
{{See also|Hallmarks of aging#Mitochondrial dysfunction}}

There may be some leakage of the [[Electron transport chain|electrons transferred]] in the respiratory chain to form [[reactive oxygen species]]. This was thought to result in significant [[oxidative stress]] in the mitochondria with high mutation rates of mitochondrial DNA.<ref>{{cite journal | vauthors = Richter C, Park JW, Ames BN | title = Normal oxidative damage to mitochondrial and nuclear DNA is extensive | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 17 | pages = 6465–6467 | date = September 1988 | pmid = 3413108 | pmc = 281993 | doi = 10.1073/pnas.85.17.6465 | doi-access = free | bibcode = 1988PNAS...85.6465R }}</ref> Hypothesized links between aging and oxidative stress are not new and were proposed in 1956,<ref>{{cite journal | vauthors = Harman D | title = Aging: a theory based on free radical and radiation chemistry | journal = Journal of Gerontology | volume = 11 | issue = 3 | pages = 298–300 | date = July 1956 | pmid = 13332224 | doi = 10.1093/geronj/11.3.298 | citeseerx = 10.1.1.663.3809 }}</ref> which was later refined into the [[Mitochondrial theory of ageing|mitochondrial free radical theory of aging]].<ref>{{cite journal | vauthors = Harman D | title = The biologic clock: the mitochondria? | journal = Journal of the American Geriatrics Society | volume = 20 | issue = 4 | pages = 145–147 | date = April 1972 | pmid = 5016631 | doi = 10.1111/j.1532-5415.1972.tb00787.x }}</ref> A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress.

A number of changes can occur to mitochondria during the aging process.<ref>{{cite web |url= http://www.circuitblue.com/biogerontology/mito.shtml |title= Mitochondria and Aging |publisher= circuitblue.co |access-date= October 23, 2006 |archive-date= September 29, 2017 |archive-url= https://web.archive.org/web/20170929210338/http://circuitblue.com/biogerontology/mito.shtml |url-status= live }}</ref> Tissues from elderly humans show a decrease in enzymatic activity of the proteins of the respiratory chain.<ref>{{cite journal | vauthors = Boffoli D, Scacco SC, Vergari R, Solarino G, Santacroce G, Papa S | title = Decline with age of the respiratory chain activity in human skeletal muscle | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1226 | issue = 1 | pages = 73–82 | date = April 1994 | pmid = 8155742 | doi = 10.1016/0925-4439(94)90061-2 }}</ref> However, mutated mtDNA can only be found in about 0.2% of very old cells.<ref>{{cite journal | vauthors = de Grey AD | title = Mitochondrial mutations in mammalian aging: an over-hasty about-turn? | journal = Rejuvenation Research | volume = 7 | issue = 3 | pages = 171–174 | year = 2004 | pmid = 15588517 | doi = 10.1089/rej.2004.7.171 }}</ref> Large deletions in the mitochondrial genome have been hypothesized to lead to high levels of [[oxidative stress]] and neuronal death in [[Parkinson's disease]].<ref>{{cite journal | vauthors = Bender A, Krishnan KJ, Morris CM, Taylor GA, Reeve AK, Perry RH, Jaros E, Hersheson JS, Betts J, Klopstock T, Taylor RW, Turnbull DM | title = High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease | journal = Nature Genetics | volume = 38 | issue = 5 | pages = 515–517 | date = May 2006 | pmid = 16604074 | doi = 10.1038/ng1769 }}</ref> Mitochondrial dysfunction has also been shown to occur in [[amyotrophic lateral sclerosis]].<ref>{{cite journal | vauthors = Mehta AR, Walters R, Waldron FM, Pal S, Selvaraj BT, Macleod MR, Hardingham GE, Chandran S, Gregory JM | title = Targeting mitochondrial dysfunction in amyotrophic lateral sclerosis: a systematic review and meta-analysis | journal = Brain Communications | volume = 1 | issue = 1 | pages = fcz009 | date = August 2019 | pmid = 32133457 | pmc = 7056361 | doi = 10.1093/braincomms/fcz009 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mehta AR, Gregory JM, Dando O, Carter RN, Burr K, Nanda J, Story D, McDade K, Smith C, Morton NM, Mahad DJ, Hardingham GE, Chandran S, Selvaraj BT | title = Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis | journal = Acta Neuropathologica | volume = 141 | issue = 2 | pages = 257–279 | date = February 2021 | pmid = 33398403 | pmc = 7847443 | doi = 10.1007/s00401-020-02252-5 | doi-access = free }}</ref>

Since mitochondria cover a pivotal role in the ovarian function, by providing ATP necessary for the development from germinal vesicle to mature [[oocyte]], a decreased mitochondria function can lead to inflammation, resulting in premature ovarian failure and accelerated ovarian aging. The resulting dysfunction is then reflected in quantitative (such as mtDNA copy number and mtDNA deletions), qualitative (such as mutations and strand breaks) and oxidative damage (such as dysfunctional mitochondria due to ROS), which are not only relevant in ovarian aging, but perturb oocyte-cumulus crosstalk in the ovary, are linked to genetic disorders (such as Fragile X) and can interfere with embryo selection.<ref>{{cite journal | vauthors = Chiang JL, Shukla P, Pagidas K, Ahmed NS, Karri S, Gunn DD, Hurd WW, Singh KK | title = Mitochondria in Ovarian Aging and Reproductive Longevity | journal = Ageing Research Reviews | volume = 63 | pages = 101168 | date = November 2020 | pmid = 32896666 | pmc = 9375691 | doi = 10.1016/j.arr.2020.101168 }}</ref>