Editing Mitochondrial DNA (section)

=== Neurodegenerative diseases ===

Increased mt[[DNA damage (naturally occurring)|DNA damage]] is a feature of several [[neurodegeneration|neurodegenerative diseases]].

The brains of individuals with [[Alzheimer's disease]] have elevated levels of [[DNA oxidation|oxidative DNA damage]] in both [[nuclear DNA]] and mtDNA, but the mtDNA has approximately 10-fold higher levels than nuclear DNA.<ref name="pmid15857398">{{Cite journal |vauthors=Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA |date=May 2005 |title=Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease |journal=Journal of Neurochemistry |volume=93 |issue=4 |pages=953–962 |doi=10.1111/j.1471-4159.2005.03053.x |pmid=15857398 |doi-access=free}}</ref> It has been proposed that aged [[mitochondrion|mitochondria]] is the critical factor in the origin of neurodegeneration in Alzheimer's disease.<ref name="pmid24733654">{{Cite journal |vauthors=Bonda DJ, Wang X, Lee HG, Smith MA, Perry G, Zhu X |date=April 2014 |title=Neuronal failure in Alzheimer's disease: a view through the oxidative stress looking-glass |journal=Neuroscience Bulletin |volume=30 |issue=2 |pages=243–252 |doi=10.1007/s12264-013-1424-x |pmc=4097013 |pmid=24733654}}</ref> Analysis of the brains of AD patients suggested an impaired function of the [[DNA repair]] pathway, which would cause reduce the overall quality of mtDNA.<ref>{{Cite journal |vauthors=Canugovi C, Shamanna RA, Croteau DL, Bohr VA |date=June 2014 |title=Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease |journal=Neurobiology of Aging |volume=35 |issue=6 |pages=1293–1300 |doi=10.1016/j.neurobiolaging.2014.01.004 |pmc=5576885 |pmid=24485507}}</ref>

In [[Huntington's disease]], mutant [[huntingtin protein]] causes [[mitochondrial dysfunction]] involving inhibition of [[mitochondrial]] [[electron transport chain|electron transport]], higher levels of [[reactive oxygen species]] and increased [[oxidative stress]].<ref name="pmid28785371">{{Cite journal |vauthors=Liu Z, Zhou T, Ziegler AC, Dimitrion P, Zuo L |date=2017 |title=Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications |journal=Oxidative Medicine and Cellular Longevity |volume=2017 |page=2525967 |doi=10.1155/2017/2525967 |pmc=5529664 |pmid=28785371 |doi-access=free}}</ref> Mutant huntingtin protein promotes oxidative damage to mtDNA, as well as nuclear DNA, that may contribute to Huntington's disease [[pathology]].<ref name="pmid23602907">{{Cite journal |vauthors=Ayala-Peña S |date=September 2013 |title=Role of oxidative DNA damage in mitochondrial dysfunction and Huntington's disease pathogenesis |journal=Free Radical Biology & Medicine |volume=62 |pages=102–110 |doi=10.1016/j.freeradbiomed.2013.04.017 |pmc=3722255 |pmid=23602907}}</ref>

The [[DNA oxidation]] product [[8-oxoguanine]] (8-oxoG) is a well-established marker of oxidative DNA damage.  In persons with [[amyotrophic lateral sclerosis]] (ALS), the enzymes that normally repair 8-oxoG DNA damages in the mtDNA of spinal [[motor neuron]]s are impaired.<ref name="pmid11904761">{{Cite journal |vauthors=Kikuchi H, Furuta A, Nishioka K, Suzuki SO, Nakabeppu Y, Iwaki T |date=April 2002 |title=Impairment of mitochondrial DNA repair enzymes against the accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis |journal=Acta Neuropathologica |volume=103 |issue=4 |pages=408–414 |doi=10.1007/s00401-001-0480-x |pmid=11904761 |s2cid=2102463}}</ref> Thus oxidative damage to mtDNA of motor neurons may be a significant factor in the [[etiology]] of ALS.{{cn|date=November 2024}}