Quantitative Mapping of Reversible Mitochondrial Complex I Cysteine Oxidation in a Parkinson Disease Mouse Model

Danielson, Steven R.; Held, Jason M.; Oo, May; Riley, Rebeccah; Gibson, Bradford W.; Andersen, Julie K.

doi:10.1074/jbc.m110.190108

Cited by 55 publications

(43 citation statements)

References 38 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MnTBAP restored the protein levels of representative subunits of mitochondrial OXPHOS complexes I and III in UCP-DTA hearts. These complexes are the main sites of mitochondrial ROS generation [41], and the damage to specific subunits or iron-sulfur clusters may make them susceptible to oxidative damage and degradation or improper assembly [42]. Reduced expression of mitochondrial OXPHOS complex I, mitochondrial dysfunction and overflow of ROS was previously documented in the hearts and skeletal muscle of insulin resistant and obese mice and humans, respectively [4, 43].…”

Section: Discussionmentioning

confidence: 99%

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Ilkun

Wilde

Tuinei

et al. 2015

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.

show abstract

Section: Discussionmentioning

confidence: 99%

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Ilkun

Wilde

Tuinei

et al. 2015

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…In dopaminergic neurons and model cells, oxidative and nitrosative stress causes preferential inhibition of complex I activity and extensive accumulation of S-nitrosothiols in mitochondrial proteins, with many modifications occurring in complex I (55,67,71). A recent proteomics study in an animal model of PD identified 34 distinct cysteine residues in the components of complex I (26% of total thiol groups), which are modified during disease progression in vivo (68). S-nitrosating compounds, such as S-nitroso-l-cysteine, strongly inhibit mitochondrial O 2 consumption and ATP production in isolated brain nerve endings (synaptosomes) and in neuronal cells (34,81,222).…”

Section: The Mitochondrial Electron Transport Chainmentioning

confidence: 99%

Selective Vulnerability of Synaptic Signaling and Metabolism to Nitrosative Stress

Mongin

Dohare

Jourd’heuil

2012

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Nitric oxide (NO) plays diverse physiological roles in the central nervous system, where it modulates neuronal communication, regulates blood flow, and contributes to the innate immune responses. In a number of brain pathologies, the excessive production of NO also leads to the formation of reactive and toxic intermediates generically termed reactive nitrogen species (RNS). RNS cause irreversible or poorly reversible damage to brain cells. Recent Advances: Recent work in the field focused on the ability of NO and RNS to yield protein modifications, including the S-nitrosation of cysteine residues, which, in many instances, impact cellular functions and viability. Critical Issues: The vast majority of neuropathological studies focus on the loss of cell viability, but nitrosative stress may also strongly impair the functions of neuronal processes: axonal projections and dendritic trees. The functional integrity of axons and dendrites critically depends on local metabolism and effective delivery of metabolic enzymes and organelles. Here, we summarize the existing literature describing the effects of nitrosative stress on the major pathways of energetic metabolism: glycolysis, tricarboxylic acid cycle, and mitochondrial respiration, with the emphasis on modifications of protein thiols. Future Directions: We propose that axons and dendrites are highly vulnerable to nitrosative stress because of their low glycolytic capacity and high dependence on timely delivery of metabolic enzymes and organelles from the cell body. Thus, supplementation with the end products of glycolysis, pyruvate or lactate, may help preserve metabolism in distal neuronal processes and protect or restore synaptic function in the ailing brain. Antioxid. Redox Signal. 17, 992-1012.

show abstract

“…52,53 The degree to which this process can affect protein activity, varies according to the role and importance of the cysteine residue for carrying out protein function, regardless of glutathione, but still under reversible redox control or, alternatively, as a result of oxidative damage. 54,55 Thus, Meth as a ROS-inducer and trigger, and NAC as a controller, can potentially be acting on the same residues, but in different ways. BAT is a tissue that may be particularly sensitive to such mechanism, for being a high redox environment with a high mitochondrial content.…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice

et al. 2014

View full text Add to dashboard Cite

Hyperthermia is a potentially lethal side effect of Methamphetamine (Meth) abuse, which involves the participation of peripheral thermogenic sites such as the Brown Adipose Tissue (BAT). In a previous study we found that the anti-oxidant N-acetyl cysteine (NAC) can prevent the high increase in temperature in a mouse model of Meth-hyperthermia. Here, we have further explored the ability of NAC to modulate Meth-induced hyperthermia in correlation with changes in BAT. We found that NAC treatment in controls causes hypothermia, and, when administered prior or upon the onset of Meth-induced hyperthermia, can ameliorate the temperature increase and preserve mitochondrial numbers and integrity, without affecting locomotor activity. This was different from Dantrolene, which decreased motor activity without affecting temperature. The effects of NAC were seen in spite of its inability to recover the decrease of mitochondrial superoxide induced in BAT by Meth. In addition, NAC did not prevent the Meth-induced decrease of BAT glutathione. Treatment with S-adenosyl-L-methionine, which improves glutathione activity, had an effect in ameliorating Meth-induced hyperthermia, but also modulated motor activity. This suggests a role for the remaining glutathione for controlling temperature. However, the mechanism by which NAC operates is independent of glutathione levels in BAT and specific to temperature. Our results show that, in spite of the absence of a clear mechanism of action, NAC is a pharmacological tool to examine the dissociation between Meth-induced hyperthermia and motor activity, and a drug of potential utility in treating the hyperthermia associated with Meth-abuse.

show abstract

Quantitative Mapping of Reversible Mitochondrial Complex I Cysteine Oxidation in a Parkinson Disease Mouse Model

Cited by 55 publications

References 38 publications

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome

Selective Vulnerability of Synaptic Signaling and Metabolism to Nitrosative Stress

Reactive oxygen species scavenger N-acetyl cysteine reduces methamphetamine-induced hyperthermia without affecting motor activity in mice

Contact Info

Product

Resources

About