A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria

Pryde, Kenneth R.; Taanman, Jan‐Willem; Schapira, Anthony H.V.

doi:10.1016/j.celrep.2016.11.027

Cited by 95 publications

(84 citation statements)

References 41 publications

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“…We have recently demonstrated that mild inhibition of complex I caused by nitrite‐mediated complex I S‐nitrosation is protective in multiple models of PD and improves bioenergetic efficiency in the fibroblasts of PD patients, but not in matched controls . A protective role for mitochondrial suppression is further substantiated by other independent studies that have shown that the reversible complex I inhibitor Mitochondrial division inhibitor 1 (Mdivi‐1) is protective in PD animal models and that proteolytic degradation of complex I attenuates ROS production in damaged, depolarized mitochondria . In addition, it has been shown that fibroblasts from patients harboring mutations in the PD‐associated gene ATPase cation transporting 13A2 ( ATP13A2 ) display higher, rather than lower, mitochondrial oxygen consumption, which is in turn associated with multiple mitochondrial anomalies .…”

Section: Discussionmentioning

confidence: 91%

“…12 A protective role for mitochondrial suppression is further substantiated by other independent studies that have shown that the reversible complex I inhibitor Mitochondrial division inhibitor 1 (Mdivi-1) 35 is protective in PD animal models 11,13 and that proteolytic degradation of complex I attenuates ROS production in damaged, depolarized mitochondria. 36 In addition, it has been shown that fibroblasts from patients harboring mutations in the PD-associated gene ATPase cation transporting 13A2 (ATP13A2) display higher, rather than lower, mitochondrial oxygen consumption, which is in turn associated with multiple mitochondrial anomalies. 37 Together with the evidence presented in this study, these data suggest that-at least in some subtypes of PD-mitochondrial function could be an amenable target for disease modification.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

et al. 2019

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Background Parkinson's disease is an intractable disorder with heterogeneous clinical presentation that may reflect different underlying pathogenic mechanisms. Surrogate indicators of pathogenic processes correlating with clinical measures may assist in better patient stratification. Mitochondrial function, which is impaired in and central to PD pathogenesis, may represent one such surrogate indicator. Methods Mitochondrial function was assessed by respirometry experiment in fibroblasts derived from idiopathic patients (n = 47) in normal conditions and in experimental settings that do not permit glycolysis and therefore force energy production through mitochondrial function. Respiratory parameters and clinical measures were correlated with bivariate analysis. Machine‐learning‐based classification and regression trees were used to classify patients on the basis of biochemical and clinical measures. The effects of mitochondrial respiration on α‐synuclein stress were assessed monitoring the protein phosphorylation in permitting versus restrictive glycolysis conditions. Results Bioenergetic properties in peripheral fibroblasts correlate with clinical measures in idiopathic patients, and the correlation is stronger with predominantly nondopaminergic signs. Bioenergetic analysis under metabolic stress, in which energy is produced solely by mitochondria, shows that patients’ fibroblasts can augment respiration, therefore indicating that mitochondrial defects are reversible. Forcing energy production through mitochondria, however, favors α‐synuclein stress in different cellular experimental systems. Machine‐learning‐based classification identified different groups of patients in which increasing disease severity parallels higher mitochondrial respiration. Conclusion The suppression of mitochondrial activity in PD may be an adaptive strategy to cope with concomitant pathogenic factors. Moreover, mitochondrial measures in fibroblasts are potential peripheral biomarkers to follow disease progression. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

et al. 2019

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“…Another, more intriguing possibility is that complex I is actively downregulated as a compensatory response to moderate excess generation of reactive oxygen species (ROS). Evidence of increased oxidative damage has been consistently found in the PD brain [1,45] and it has been shown that, under certain conditions, complex I inhibition [28] or modulation [29] can substantially decrease ROS generation. Irrespective of whether it is a pathogenic event or compensatory response, the extent of neuronal complex I deficiency in PD suggests that it is an important and inherent part of the disorder.…”

Section: Discussionmentioning

confidence: 99%

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

et al. 2017

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Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can occur independently of mitochondrial DNA damage and may not have a pathogenic role in the neurodegenerative process.

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“…Our results suggest that the previously reported transcriptional down-regulation of the respiratory chain is at least partly driven by altered cellular composition (due to decreased number of neurons which highly express these genes) and may therefore not be the sole mechanism by which neuronal complex I deficiency occurs in PD. Indeed, it has been suggested that complex I deficiency in PD may be mediated by proteolytic degradation by the LON-ClpP protease system, rather than transcriptional regulation [30].…”

Section: Discussionmentioning

confidence: 99%

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

Nido

Dick

Toker

et al. 2019

Preprint

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AbstractBackgroundThe etiology of Parkinson’s disease (PD) is largely unknown. Genome-wide transcriptomic studies in bulk brain tissue have identified several molecular signatures associated with the disease. While these studies have the potential to shed light into the pathogenesis of PD, they are also limited by two major confounders: RNA post mortem degradation and heterogeneous cell type composition of bulk tissue samples. We performed RNA sequencing following ribosomal RNA depletion in the prefrontal cortex of 49 individuals from two independent case-control cohorts. Using cell-type specific markers, we estimated the cell-type composition for each sample and included this in our analysis models to compensate for the variation in cell-type proportions.ResultsRibosomal RNA depletion results in substantially more even transcript coverage, compared to poly(A) capture, in post mortem tissue. Moreover, we show that cell-type composition is a major confounder of differential gene expression analysis in the PD brain. Correcting for cell-type proportions attenuates numerous transcriptomic signatures that have been previously associated with PD, including vesicle trafficking, synaptic transmission, immune and mitochondrial function. Conversely, pathways related to endoplasmic reticulum, lipid oxidation and unfolded protein response are strengthened and surface as the top differential gene expression signatures in the PD prefrontal cortex.ConclusionsDifferential gene expression signatures in PD bulk brain tissue are significantly confounded by underlying differences in cell-type composition. Modeling cell-type heterogeneity is crucial in order to unveil transcriptomic signatures that represent regulatory changes in the PD brain and are, therefore, more likely to be associated with underlying disease mechanisms.

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A LON-ClpP Proteolytic Axis Degrades Complex I to Extinguish ROS Production in Depolarized Mitochondria

Cited by 95 publications

References 41 publications

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

Peripheral mitochondrial function correlates with clinical severity in idiopathic Parkinson's disease

Neuronal complex I deficiency occurs throughout the Parkinson’s disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage

Common gene expression signatures in Parkinson’s disease are driven by changes in cell composition

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