A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

Maddison, Daniel C.; Alfonso-Núñez, Mónica; Swaih, Aisha M.; Breda, Carlo; Campesan, Susanna; Allcock, Natalie; Straatman-Iwanowska, Anna; Kyriacou, Charalambos P.; Giorgini, Flaviano

doi:10.1371/journal.pgen.1009129

Cited by 13 publications

(22 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is, however, possible that LhCn has other biological roles in L. hesperus. The homologous Cn gene in D. melanogaster modulates post-translational regulation of the mitochondrial fission gene Drp1 , such that disruption of Cn activity negatively impacts mitochondrial morphology and function 38 . However, we have not observed any changes in L. hesperus beyond eye color in this or our previous study of LhCn 28 .…”

Section: Discussionmentioning

confidence: 99%

CRISPR-mediated knockout of cardinal and cinnabar eye pigmentation genes in the western tarnished plant bug

Heu

Gross

et al. 2022

Sci Rep

View full text Add to dashboard Cite

The western tarnished plant bug, Lygus hesperus, is a key hemipteran pest of numerous agricultural, horticultural, and industrial crops in the western United States and Mexico. A lack of genetic tools in L. hesperus hinders progress in functional genomics and in developing innovative pest control methods such as gene drive. Here, using RNA interference (RNAi) against cardinal (LhCd), cinnabar (LhCn), and white (LhW), we showed that knockdown of LhW was lethal to developing embryos, while knockdown of LhCd or LhCn produced bright red eye phenotypes, in contrast to wild-type brown eyes. We further used CRISPR/Cas9 (clustered regularly interspaced palindromic repeats/CRISPR-associated) genome editing to generate germline knockouts of both LhCd (Card) and LhCn (Cinn), producing separate strains of L. hesperus characterized by mutant eye phenotypes. Although the cardinal knockout strain Card exhibited a gradual darkening of the eyes to brown typical of the wild-type line later in nymphal development, we observed bright red eyes throughout all life stages in the cinnabar knockout strain Cinn, making it a viable marker for tracking gene editing in L. hesperus. These results provide evidence that CRISPR/Cas9 gene editing functions in L. hesperus and that eye pigmentation genes are useful for tracking the successful genetic manipulation of this insect.

show abstract

Section: Discussionmentioning

confidence: 99%

CRISPR-mediated knockout of cardinal and cinnabar eye pigmentation genes in the western tarnished plant bug

Heu

Gross

et al. 2022

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This indicates that KMO activity may have the opposite effects for neurons. Its moderate activation may promote favorable bioenergetics processes, but excessive activation would deplete energy stores and induce cell damage, leading to its dysfunction [ 104 , 201 , 202 , 203 ]. This mechanism seems to be important in terms of neurodegenerative diseases because neurons are highly sensitive to oxidative stress, energy depletion, and mitochondrial impairment ( Table 2 ) [ 201 , 202 , 203 ].…”

Section: Enzymes Of the Kynurenine Pathway And The Possibility Of Pharmacological Modulation Of Their Activitymentioning

confidence: 99%

“…Its moderate activation may promote favorable bioenergetics processes, but excessive activation would deplete energy stores and induce cell damage, leading to its dysfunction [ 104 , 201 , 202 , 203 ]. This mechanism seems to be important in terms of neurodegenerative diseases because neurons are highly sensitive to oxidative stress, energy depletion, and mitochondrial impairment ( Table 2 ) [ 201 , 202 , 203 ]. Therefore, pharmacological inhibition of KMO activity seems to be a promising therapeutic tool in the management of various neurodegenerative disorders [ 104 , 163 , 201 ].…”

Section: Enzymes Of the Kynurenine Pathway And The Possibility Of Pharmacological Modulation Of Their Activitymentioning

confidence: 99%

“…This mechanism seems to be important in terms of neurodegenerative diseases because neurons are highly sensitive to oxidative stress, energy depletion, and mitochondrial impairment ( Table 2 ) [ 201 , 202 , 203 ]. Therefore, pharmacological inhibition of KMO activity seems to be a promising therapeutic tool in the management of various neurodegenerative disorders [ 104 , 163 , 201 ]. As mentioned above, the inhibition of IDO and QPRT activity may reduce the viability of astrocytes and neurons and exacerbate the clinical and histologic disease parameters during experimental autoimmune encephalomyelitis.…”

Section: Enzymes Of the Kynurenine Pathway And The Possibility Of Pharmacological Modulation Of Their Activitymentioning

confidence: 99%

See 1 more Smart Citation

Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Mor

Tankiewicz-Kwedlo

Krupa

et al. 2021

Cells

View full text Add to dashboard Cite

Neurodegenerative disorders are chronic and life-threatening conditions negatively affecting the quality of patients’ lives. They often have a genetic background, but oxidative stress and mitochondrial damage seem to be at least partly responsible for their development. Recent reports indicate that the activation of the kynurenine pathway (KP), caused by an activation of proinflammatory factors accompanying neurodegenerative processes, leads to the accumulation of its neuroactive and pro-oxidative metabolites. This leads to an increase in the oxidative stress level, which increases mitochondrial damage, and disrupts the cellular energy metabolism. This significantly reduces viability and impairs the proper functioning of central nervous system cells and may aggravate symptoms of many psychiatric and neurodegenerative disorders. This suggests that the modulation of KP activity could be effective in alleviating these symptoms. Numerous reports indicate that tryptophan supplementation, inhibition of KP enzymes, and administration or analogs of KP metabolites show promising results in the management of neurodegenerative disorders in animal models. This review gathers and systematizes the knowledge concerning the role of metabolites and enzymes of the KP in the development of oxidative damage within brain cells during neurodegenerative disorders and potential strategies that could reduce the severity of this process.

show abstract

“…Importantly, because of its pivotal position in the KP, KMO is not only critical for 3-HK formation but controls the synthesis of several other biologically active KP metabolites, including kynurenic acid (KYNA), xanthurenic acid, 3-hydroxyanthranilic acid, xanthurenic acid, quinolinic acid, picolinic acid and cinnabarinic acid [ 1 ]. An NADPH-dependent enzyme located in the outer mitochondrial membrane [ 2 , 3 , 4 ] and linked to mitochondrial function [ 5 ], KMO is widely expressed in peripheral tissues, macrophages and monocytes [ 6 , 7 ]. Notably, as a number of KP metabolites are increasingly perceived to have considerable significance in normal brain function (see [ 8 ], for review), impaired KMO activity may play a substantive role in the pathophysiology of several neurological and psychiatric diseases [ 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma

et al. 2022

Self Cite

View full text Add to dashboard Cite

Kynurenine 3-monooxygenase (KMO), a key player in the kynurenine pathway (KP) of tryptophan degradation, regulates the synthesis of the neuroactive metabolites 3-hydroxykynurenine (3-HK) and kynurenic acid (KYNA). KMO activity has been implicated in several major brain diseases including Huntington’s disease (HD) and schizophrenia. In the brain, KMO is widely believed to be predominantly localized in microglial cells, but verification in vivo has not been provided so far. Here, we examined KP metabolism in the brain after depleting microglial cells pharmacologically with the colony stimulating factor 1 receptor inhibitor PLX5622. Young adult mice were fed PLX5622 for 21 days and were euthanized either on the next day or after receiving normal chow for an additional 21 days. Expression of microglial marker genes was dramatically reduced on day 22 but had fully recovered by day 43. In both groups, PLX5622 treatment failed to affect Kmo expression, KMO activity or tissue levels of 3-HK and KYNA in the brain. In a parallel experiment, PLX5622 treatment also did not reduce KMO activity, 3-HK and KYNA in the brain of R6/2 mice (a model of HD with activated microglia). Finally, using freshly isolated mouse cells ex vivo, we found KMO only in microglia and neurons but not in astrocytes. Taken together, these data unexpectedly revealed that neurons contain a large proportion of functional KMO in the adult mouse brain under both physiological and pathological conditions.

show abstract

A novel role for kynurenine 3-monooxygenase in mitochondrial dynamics

Cited by 13 publications

References 82 publications

CRISPR-mediated knockout of cardinal and cinnabar eye pigmentation genes in the western tarnished plant bug

CRISPR-mediated knockout of cardinal and cinnabar eye pigmentation genes in the western tarnished plant bug

Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders

Cellular Localization of Kynurenine 3-Monooxygenase in the Brain: Challenging the Dogma

Contact Info

Product

Resources

About