Editing Respiratory complex I (section)

==Pathology==
Mutations in the subunits of complex I can cause [[mitochondrial diseases]], including [[Leigh syndrome]]. Point mutations in various complex I subunits derived from mitochondrial DNA ([[mtDNA]]) can also result in [[Leber's Hereditary Optic Neuropathy]].There is some evidence that complex I defects may play a role in the etiology of [[Parkinson's disease]], perhaps because of reactive oxygen species (complex I can, like [[complex III]], leak electrons to oxygen, forming highly toxic [[superoxide]]).

Although the exact etiology of Parkinson's disease is unclear, it is likely that mitochondrial dysfunction, along with proteasome inhibition and environmental toxins, may play a large role. In fact, the inhibition of complex I has been shown to cause the production of peroxides and a decrease in [[proteasome]] activity, which may lead to Parkinson's disease.<ref name="pmid20417232">{{cite journal | vauthors = Chou AP, Li S, Fitzmaurice AG, Bronstein JM | title = Mechanisms of rotenone-induced proteasome inhibition | journal = Neurotoxicology | volume = 31 | issue = 4 | pages = 367–72 | date = August 2010 | pmid = 20417232 | pmc = 2885979 | doi = 10.1016/j.neuro.2010.04.006 }}</ref> Additionally, Esteves et al. (2010) found that cell lines with Parkinson's disease show increased proton leakage in complex I, which causes decreased maximum respiratory capacity.<ref name="pmid20132468">{{cite journal | vauthors = Esteves AR, Lu J, Rodova M, Onyango I, Lezi E, Dubinsky R, Lyons KE, Pahwa R, Burns JM, Cardoso SM, Swerdlow RH | title = Mitochondrial respiration and respiration-associated proteins in cell lines created through Parkinson's subject mitochondrial transfer | journal = Journal of Neurochemistry | volume = 113 | issue = 3 | pages = 674–82 | date = May 2010 | pmid = 20132468 | doi = 10.1111/j.1471-4159.2010.06631.x | doi-access = free }}</ref>

Brain ischemia/reperfusion injury is mediated via complex I impairment.<ref>{{cite journal | vauthors = Galkin A | title = Brain Ischemia/Reperfusion Injury and Mitochondrial Complex I Damage | journal = Biochemistry. Biokhimiia | volume = 84 | issue = 11 | pages = 1411–1423 | date = November 2019 | pmid = 31760927 | doi = 10.1134/S0006297919110154 | s2cid = 207990089 }}</ref> Recently it was found that oxygen deprivation leads to conditions in which mitochondrial complex I lose its natural cofactor, flavin mononucleotide (FMN) and become inactive.<ref>{{cite journal | vauthors = Kahl A, Stepanova A, Konrad C, Anderson C, Manfredi G, Zhou P, Iadecola C, Galkin A | display-authors = 6 | title = Critical Role of Flavin and Glutathione in Complex I-Mediated Bioenergetic Failure in Brain Ischemia/Reperfusion Injury | journal = Stroke | volume = 49 | issue = 5 | pages = 1223–1231 | date = May 2018 | pmid = 29643256 | pmc = 5916474 | doi = 10.1161/STROKEAHA.117.019687 }}</ref><ref name=":1">{{cite journal | vauthors = Stepanova A, Sosunov S, Niatsetskaya Z, Konrad C, Starkov AA, Manfredi G, Wittig I, Ten V, Galkin A | display-authors = 6 | title = Redox-Dependent Loss of Flavin by Mitochondrial Complex I in Brain Ischemia/Reperfusion Injury | journal = Antioxidants & Redox Signaling | volume = 31 | issue = 9 | pages = 608–622 | date = September 2019 | pmid = 31037949 | pmc = 6657304 | doi = 10.1089/ars.2018.7693 }}</ref> When oxygen is present the enzyme catalyzes a physiological reaction of NADH oxidation by ubiquinone, supplying electrons downstream of the respiratory chain (complexes III and IV). Ischemia leads to dramatic increase of [[Succinic acid|succinate]] level. In the presence of succinate mitochondria catalyze reverse electron [[Reverse electron flow|transfer]] so that fraction of electrons from succinate is directed upstream to FMN of complex I. Reverse electron transfer results in a reduction of complex I FMN,<ref name="Reverse electron transfer results i"/> increased generation of ROS, followed by a loss of the reduced cofactor (FMNH<sub>2</sub>) and impairment of mitochondria energy production. The FMN loss by complex I and I/R injury can be alleviated by the administration of FMN precursor, riboflavin.<ref name=":1" />

Recent studies have examined other roles of complex I activity in the brain. Andreazza et al. (2010) found that the level of complex I activity was significantly decreased in patients with bipolar disorder, but not in patients with depression or schizophrenia. They found that patients with bipolar disorder showed increased protein oxidation and nitration in their prefrontal cortex. These results suggest that future studies should target complex I for potential therapeutic studies for bipolar disorder.<ref name="pmid20368511">{{cite journal | vauthors = Andreazza AC, Shao L, Wang JF, Young LT | title = Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder | journal = Archives of General Psychiatry | volume = 67 | issue = 4 | pages = 360–8 | date = April 2010 | pmid = 20368511 | doi = 10.1001/archgenpsychiatry.2010.22 | doi-access = free }}</ref> Similarly, Moran et al. (2010) found that patients with severe complex I deficiency showed decreased oxygen consumption rates and slower growth rates. However, they found that mutations in different genes in complex I lead to different phenotypes, thereby explaining the variations of pathophysiological manifestations of complex I deficiency.<ref name="pmid20153825">{{cite journal | vauthors = Morán M, Rivera H, Sánchez-Aragó M, Blázquez A, Merinero B, Ugalde C, Arenas J, Cuezva JM, Martín MA | title = Mitochondrial bioenergetics and dynamics interplay in complex I-deficient fibroblasts | journal = Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | volume = 1802 | issue = 5 | pages = 443–53 | date = May 2010 | pmid = 20153825 | doi = 10.1016/j.bbadis.2010.02.001 | doi-access = free }}</ref>

Exposure to pesticides can also inhibit complex I and cause disease symptoms. For example, chronic exposure to low levels of dichlorvos, an organophosphate used as a pesticide, has been shown to cause liver dysfunction. This occurs because dichlorvos alters complex I and II activity levels, which leads to decreased mitochondrial electron transfer activities and decreased ATP synthesis.<ref name="pmid 20132858">{{cite journal | vauthors = Binukumar BK, Bal A, Kandimalla R, Sunkaria A, Gill KD | title = Mitochondrial energy metabolism impairment and liver dysfunction following chronic exposure to dichlorvos | journal = Toxicology | volume = 270 | issue = 2–3 | pages = 77–84 | date = April 2010 | pmid = 20132858 | doi = 10.1016/j.tox.2010.01.017 }}</ref>