Monoamine oxidase‐A knockdown in human neuroblastoma cells reveals protection against mitochondrial toxins

Fitzgerald, Julia C.; Ugun-Klusek, Aslihan; Allen, Geoffrey; Girolamo, Luigi A. De; Hargreaves, Iain P.; Ufer, Christoph; Abramov, Andrey Y.; Billett, E. Ellen

doi:10.1096/fj.13-235481

Cited by 34 publications

(20 citation statements)

References 56 publications

(73 reference statements)

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“…Increased DOPAL formation in this setting contributes to rotenone-induced cytotoxicity (Lamensdorf et al, 2000b). Knockdown of MAO-A mitigates rotenone-induced apoptosis (Fitzgerald et al, 2014), consistent with DOPAL, hydrogen peroxide, or both contributing to the toxicity of this pesticide.…”

Section: Aldehyde Detoxification and Catecholamine Autotoxicitymentioning

confidence: 72%

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Goldstein

Kopin

Sharabi

2014

Pharmacology & Therapeutics

138

121

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Several neurodegenerative diseases involve loss of catecholamine neurons—Parkinson disease is a prototypical example. Catecholamine neurons are rare in the nervous system, and why they are vulnerable in PD and related disorders has been mysterious. Accumulating evidence supports the concept of “autotoxicity”—inherent cytotoxicity of catecholamines and their metabolites in the cells in which they are produced. According to the “catecholaldehyde hypothesis” for the pathogenesis of Parkinson disease, long-term increased build-up of 3,4-dihydroxyphenylacetaldehyde (DOPAL), the catecholaldehyde metabolite of dopamine, causes or contributes to the eventual death of dopaminergic neurons. Lewy bodies, a neuropathologic hallmark of PD, contain precipitated alpha-synuclein. Bases for the tendency of alpha-synuclein to precipitate in the cytoplasm of catecholaminergic neurons have also been mysterious. Since DOPAL potently oligomerizes and aggregates alpha-synuclein, the catecholaldehyde hypothesis provides a link between alpha-synucleinopathy and catecholamine neuron loss in Lewy body diseases. The concept developed here is that DOPAL and alpha-synuclein are nodes in a complex nexus of interacting homeostatic systems. Dysfunctions of several processes, including decreased vesicular sequestration of cytoplasmic catecholamines, decreased aldehyde dehydrogenase activity, and oligomerization of alpha-synuclein, lead to conversion from the stability afforded by negative feedback regulation to the instability, degeneration, and system failure caused by induction of positive feedback loops. These dysfunctions result from diverse combinations of genetic predispositions, environmental exposures, stress, and time. The notion of catecholamine autotoxicity has several implications for treatment, disease modification, and prevention. Conversely, disease modification clinical trials would provide key tests of the catecholaldehyde hypothesis.

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Section: Aldehyde Detoxification and Catecholamine Autotoxicitymentioning

confidence: 72%

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Goldstein

Kopin

Sharabi

2014

Pharmacology & Therapeutics

138

121

View full text Add to dashboard Cite

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“…Moreover, since MAOs are located at the outer mitochondrial membrane, those compounds are likely to affect proteins in the vicinity, such as Pink1, parkin or the mitofusins, which are involved in mitochondrial quality control [45]. Conversely, it has been shown that MAOA knockdown in neuroblastoma SH-SY5Y cells protects against the detrimental effects of mitochondrial toxins on the respiratory chain [46]. Thus, we postulate that it is the constant degradation of catecholamines generating these toxic molecules which causes all catecholaminergic cells to be a hot spot for the generation of mtDNA deletions.…”

Section: Discussionmentioning

confidence: 99%

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

et al. 2016

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Background: Aging is a multifactorial process characterized by organ loss of function and degeneration, but the mechanisms involved remain elusive. We have shown recently that catecholamine metabolism drives the accumulation of mitochondrial DNA (mtDNA) deletions in dopaminergic cells, which likely contribute to their degeneration during aging. Here we investigated whether the well-documented degeneration and altered function of adrenals during aging is linked to catecholamine production in the medulla followed by accumulation of mtDNA deletions. Material and Methods: We analyzed adrenal medullary and cortical samples of both murine and human origin covering a wide range of ages for mtDNA deletion content, mtDNA copy number, mitochondrial and cellular integrity as well as aging-related tissue changes such as fibrosis. Results: Indeed, we demonstrate in mice and humans that the adrenal medulla accumulates a strikingly high amount of mtDNA deletions with age, causing mitochondrial dysfunction in the adrenal medulla, but also in the cortex, accompanied by apoptosis and, more importantly, by severe inflammation and remarkable fibrosis. Additionally, a concomitant and dramatic loss of medullary and cortical cells is observed in old animals. Conclusion: Our results show that accumulation of mtDNA deletions, and the ensuing mitochondrial dysfunction, is a hallmark of adrenal aging, further strengthening the hypothesis that catecholamine metabolism is detrimental to mtDNA integrity, mitochondrial function and cell survival. Moreover, the cell loss potentially induced by mitochondrial dysfunction could explain the decline in adrenal hormonal and steroidal secretion during aging.

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“…MAO plays the major role in the development of oxidative stress of the nervous system and heart. When the heart is subjected to chronic neurohumoral and/or peripheral hemodynamic stress, the attendant abundance of circulating/tissue monoamines fuels MAO-derived H 2 O 2 production and has been shown to play in I/R injury [26,32,33]. Recent results demonstrate that MAO is an important determinant of redox balance in human atrial myocardium as well [34].…”

Section: Mitochondrial Sources Of Rosmentioning

confidence: 99%

Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning

2014

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Reductions in the blood supply produce considerable injury if the duration of ischemia is prolonged. Paradoxically, restoration of perfusion to ischemic organs can exacerbate tissue damage and extend the size of an evolving infarct. Being highly metabolic organs, the heart and brain are particularly vulnerable to the deleterious effects of ischemia/reperfusion (I/R). While the pathogenetic mechanisms contributing to I/R-induced tissue injury and infarction are multifactorial, the relative importance of each contributing factor remains unclear. However, an emerging body of evidence indicates that the generation of reactive oxygen species (ROS) by mitochondria plays a critical role in damaging cellular components and initiating cell death. In this review, we summarize our current understanding of the mechanisms whereby mitochondrial ROS generation occurs in I/R and contributes to myocardial infarction and stroke. In addition, mitochondrial ROS have been shown to participate in preconditioning by several pharmacologic agents that target potassium channels (e.g., ATP-sensitive potassium (mKATP) channels or large conductance, calcium-activated potassium (mBKCa) channels) to activate cell survival programs that render tissues and organs more resistant to the deleterious effects of I/R. Finally, we review novel therapeutic approaches that selectively target mROS production to reduce postischemic tissue injury, which may prove efficacious in limiting myocardial dysfunction and infarction and abrogating neurocognitive deficits and neuronal cell death in stroke.

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Monoamine oxidase‐A knockdown in human neuroblastoma cells reveals protection against mitochondrial toxins

Cited by 34 publications

References 56 publications

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

Catecholamine Metabolism Induces Mitochondrial DNA Deletions and Leads to Severe Adrenal Degeneration during Aging

Mitochondrial reactive oxygen species: A double edged sword in ischemia/reperfusion vs preconditioning

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