Editing Mitochondrion (section)

===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>