Cellular metabolic and autophagic pathways: Traffic control by redox signaling

Dodson, Matthew; Darley‐Usmar, Victor; Zhang, Jianhua

doi:10.1016/j.freeradbiomed.2013.05.014

Cited by 298 publications

(264 citation statements)

References 210 publications

Supporting

Mentioning

254

Contrasting

Unclassified

Order By: Relevance

“…Consistent with the deleterious effects of oxidative stress, a large surge in ROS causes rapid cell death that can be associated with lysosomal membrane permeabilization. For example, neuronal death caused by the parkinsonian toxin MPP ϩ is associated with lysosomal depletion (10), possibly as a result of Fenton-like reactions involving hydrogen peroxide within lysosomes (50). In contrast, the lysosomal impairment that we observed in our models of mitochondrial dysfunction was not associated with a loss of structural proteins, such as LAMP1.…”

Section: Discussionmentioning

confidence: 75%

See 1 more Smart Citation

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

203

193

View full text Add to dashboard Cite

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases.A prominent feature of neurodegenerative diseases, including Parkinson disease (PD) 3 and Alzheimer disease, is the accumulation of undigested protein aggregates (1, 2). Although the underlying mechanisms are complex, several cellular alterations can cause aggregate accumulation, including impaired quality control pathways and the generation of reactive oxygen species (ROS) as a consequence of mitochondrial damage (1, 3).In healthy cells, protein aggregates and damaged cellular components are delivered to lysosomes to be degraded through a process termed autophagy (1, 2, 4, 5). As such, autophagy plays an important neuroprotective role. Nevertheless, the defects in degradation pathways observed in neurodegenerative diseases extend well beyond alterations in autophagy. Specifically, disruption of lysosomal function has been linked to neuronal loss in several neurodegenerative diseases. For example, mutations in the lysosomal ATPase ATP13A2 cause PD, whereas lysosomal dysfunction in Gaucher disease leads to Parkinsonism and the appearance of Lewy bodies (6, 7). In addition, the ␣-synuclein-containing Lewy bodies found in PD are positive for lysosomal markers, suggesting that they represent lysosomes that failed to degrade their content (8). In fact, lysosomal alterations are a common feature of PD (8 -11). Nevertheless, the pathological consequences of a loss of lysosomal function extend well beyond PD, because a wide variety of mutations that impair lysosomes and cause the accumulation of intracellular material (lysosomal storage diseases) show features of neurodegeneration (12).A second key metabolic pathway required for neuronal survival is mitochondrial activity. In fact, mitochondrial dysfunction is a common feature of neurodegenerative diseases. For example, decreased activity of complex I of the electron transport chain (ETC) is present in a number of PD cases (13, 14), whereas amyloid ␤, Tau tangles, and Htt aggregates all cause mitochondrial dysfunction (15-17). In addition, several genes mutated in PD (including PINK1, Parkin, and DJ-1) affect mitochondrial function and turnover (18 -21), whereas deregulation of mitochon...

show abstract

Section: Discussionmentioning

confidence: 75%

“…Because H 2 O 2 diffuses more easily than superoxide and has previously been shown to enter lysosomes and damage them through Fenton-like reactions (50), it is possible that it is H 2 O 2 that is responsible for vacuole formation. To test this, we incubated WT MEFs with glucose oxidase, which produces H 2 O 2 in the presence of glucose.…”

Section: Dmentioning

confidence: 99%

Loss of Mitochondrial Function Impairs Lysosomes

Demers-Lamarche

Guillebaud

Tlili

et al. 2016

Journal of Biological Chemistry

203

193

View full text Add to dashboard Cite

show abstract

“…Although excessive production of reactive oxygen species (ROS) from mitochondria is associated with a broad spectrum of pathologies (39 -41), there is growing evidence supporting a role of mitochondrial ROS as signaling molecules in physiological pathways (42)(43)(44)(45). In this context, mitochondrial ROS-mediated signaling cascades have been proposed to be involved in the response or adaptation to bioenergetic changes (46,47 reducing equivalents in determining the rate of mitochondrial O 2 . /H 2 O 2 production.…”

Section: Phorylation As Tools To Characterize the Contributions Of Smentioning

confidence: 99%

Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions

Wong

Dighe

Mezera

et al. 2017

Journal of Biological Chemistry

390

288

View full text Add to dashboard Cite

“…Besides, pyruvate is an effective anti-inflammatory and anti-oxidant endogenous molecule (Das 2006), suggesting that pyruvate reduction may induce cell death (Berry and Toms 2006). Changes in glucose metabolism closely correlate with pathogenesis progression and are intimately linked to redox signaling (Dodson et al 2013).…”

mentioning

confidence: 99%

Thiol/disulfide status regulates the activity of thiol-containing kinases related to energy homeostasis in rat kidney

Rech

Mezzomo

Athaydes

et al. 2017

An. Acad. Bras. Ciênc.

View full text Add to dashboard Cite

Considering that thiol-containing enzymes like kinases are critical for several metabolic pathways and energy homeostasis, we investigated the effects of cystine dimethyl ester and/or cysteamine administration on kinases crucial for energy metabolism in the kidney of Wistar rats. Animals were injected twice a day with 1.6 µmol/g body weight cystine dimethyl ester and/or 0.26 µmol/g body weight cysteamine from the 16 th to the 20 th postpartum day and euthanized after 12 hours. Pyruvate kinase, adenylate kinase, creatine kinase activities and thiol/disulfide ratio were determined. Cystine dimethyl ester administration reduced thiol/disulfide ratio and inhibited the kinases activities. Cysteamine administration increased the thiol/ disulfide ratio and co-administration with cystine dimethyl ester prevented the inhibition of the enzymes. Regression between the thiol/disulfide ratio, and the kinases activities were significant. These results suggest that redox status may regulate energy metabolism in the rat kidney. If thiol-containing enzymes inhibition and oxidative stress occur in patients with cystinosis, it is possible that lysosomal cystine depletion may not be the only beneficial effect of cysteamine administration, but also its antioxidant and thiol-protector effect.

show abstract

Cellular metabolic and autophagic pathways: Traffic control by redox signaling

Cited by 298 publications

References 210 publications

Loss of Mitochondrial Function Impairs Lysosomes

Loss of Mitochondrial Function Impairs Lysosomes

Production of superoxide and hydrogen peroxide from specific mitochondrial sites under different bioenergetic conditions

Thiol/disulfide status regulates the activity of thiol-containing kinases related to energy homeostasis in rat kidney

Contact Info

Product

Resources

About