Elevated mitochondria-coupled NAD(P)H in endoplasmic reticulum of dopamine neurons

Pyridine nucleotides are redox coenzymes that are critical in bioenergetics, metabolism, and neurodegeneration. Here we use brain slice multiphoton microscopy to show that substantia nigra dopamine neurons, which are sensitive to stress in mitochondria and the endoplasmic reticulum (ER), display elevated combined NADH and NADPH (i.e., NAD(P)H) autofluorescence. Despite limited mitochondrial mass, organellar NAD(P)H is extensive because much of the signal is derived from the ER. Remarkably, even though pyridine nucleotides cannot cross mitochondrial and ER membranes, inhibiting mitochondrial function with an uncoupler or interrupting the electron transport chain with cyanide (CN−) alters ER NAD(P)H. The ER CN− response can occur without a change in nuclear NAD(P)H, raising the possibility of redox shuttling via the cytoplasm locally between neuronal mitochondria and the ER. We propose that coregulation of NAD(P)H in dopamine neuron mitochondria and ER coordinates cell redox stress signaling by the two organelles.

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Endoplasmic reticulum stress signaling involvement in manganese-induced nerve cell damage in organotypic brain slice cultures

Toxicology Letters ◽

10.1016/j.toxlet.2013.08.001 ◽

2013 ◽

Vol 222 (3) ◽

pp. 239-246 ◽

Cited By ~ 21

Author(s):

Bin Xu ◽

Ming Shan ◽

Fei Wang ◽

Yu Deng ◽

Wei Liu ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Nerve Cell ◽

Brain Slice ◽

Cell Damage ◽

Stress Signaling ◽

Organotypic Brain Slice ◽

Brain Slice Cultures

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Faculty Opinions recommendation of Salt stress responses in Arabidopsis utilize a signal transduction pathway related to endoplasmic reticulum stress signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1096008.551993 ◽

2007 ◽

Author(s):

Ramón Serrano

Keyword(s):

Signal Transduction ◽

Endoplasmic Reticulum ◽

Salt Stress ◽

Endoplasmic Reticulum Stress ◽

Stress Responses ◽

Signal Transduction Pathway ◽

Stress Signaling ◽

Transduction Pathway

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Endoplasmic Reticulum Stress Regulators: New Drug Targets for Parkinson’s Disease

Journal of Parkinson s Disease ◽

10.3233/jpd-212673 ◽

2021 ◽

pp. 1-10

Author(s):

Vera Kovaleva ◽

Mart Saarma

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Endoplasmic Reticulum ◽

Protein Folding ◽

Er Stress ◽

Protein Misfolding ◽

Drug Targets ◽

Dopamine Neurons ◽

Drug Candidates ◽

The Unfolded Protein Response

Parkinson’s disease (PD) pathology involves progressive degeneration and death of vulnerable dopamine neurons in the substantia nigra. Extensive axonal arborisation and distinct functions make this type of neurons particularly sensitive to homeostatic perturbations, such as protein misfolding and Ca2 + dysregulation. Endoplasmic reticulum (ER) is a cell compartment orchestrating protein synthesis and folding, as well as synthesis of lipids and maintenance of Ca2 +-homeostasis in eukaryotic cells. When misfolded proteins start to accumulate in ER lumen the unfolded protein response (UPR) is activated. UPR is an adaptive signalling machinery aimed at relieving of protein folding load in the ER. When UPR is chronic, it can either boost neurodegeneration and apoptosis or cause neuronal dysfunctions. We have recently discovered that mesencephalic astrocyte-derived neurotrophic factor (MANF) exerts its prosurvival action in dopamine neurons and in animal model of PD through the direct binding to UPR sensor inositol-requiring protein 1 alpha (IRE1α) and attenuation of UPR. In line with this, UPR targeting resulted in neuroprotection and neurorestoration in various preclinical PD animal models. Therefore, growth factors (GFs), possessing both neurorestorative activity and restoration of protein folding capacity are attractive as drug candidates for PD treatment especially their blood-brain barrier penetrating analogs and small molecule mimetics. In this review, we discuss ER stress as a therapeutic target to treat PD; we summarize the existing preclinical data on the regulation of ER stress for PD treatment. In addition, we point out the crucial aspects for successful clinical translation of UPR-regulating GFs and new prospective in GFs-based treatments of PD, focusing on ER stress regulation.

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The Role of Endoplasmic Reticulum in the Differential Endurance against Redox Stress in Cortical and Spinal Astrocytes from the Newborn SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis

Antioxidants ◽

10.3390/antiox10091392 ◽

2021 ◽

Vol 10 (9) ◽

pp. 1392

Author(s):

Cecilia Marini ◽

Vanessa Cossu ◽

Mandeep Kumar ◽

Marco Milanese ◽

Katia Cortese ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Metabolic Response ◽

Early Stage ◽

Pentose Phosphate ◽

Redox Stress ◽

Als Patients ◽

Selective Enhancement ◽

Respiratory Uncoupling ◽

Lateral Sclerosis

Recent studies reported that the uptake of [18F]-fluorodeoxyglucose (FDG) is increased in the spinal cord (SC) and decreased in the motor cortex (MC) of patients with ALS, suggesting that the disease might differently affect the two nervous districts with different time sequence or with different mechanisms. Here we show that MC and SC astrocytes harvested from newborn B6SJL-Tg (SOD1G93A) 1Gur mice could play different roles in the pathogenesis of the disease. Spectrophotometric and cytofluorimetric analyses showed an increase in redox stress, a decrease in antioxidant capacity and a relative mitochondria respiratory uncoupling in MC SOD1G93A astrocytes. By contrast, SC mutated cells showed a higher endurance against oxidative damage, through the increase in antioxidant defense, and a preserved respiratory function. FDG uptake reproduced the metabolic response observed in ALS patients: SOD1G93A mutation caused a selective enhancement in tracer retention only in mutated SC astrocytes, matching the activity of the reticular pentose phosphate pathway and, thus, of hexose-6P dehydrogenase. Finally, both MC and SC mutated astrocytes were characterized by an impressive ultrastructural enlargement of the endoplasmic reticulum (ER) and impairment in ER–mitochondria networking, more evident in mutated MC than in SC cells. Thus, SOD1G93A mutation differently impaired MC and SC astrocyte biology in a very early stage of life.

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DRP1 regulates endoplasmic reticulum sheets to control mitochondrial DNA replication and segregation

10.1101/2021.12.09.472002 ◽

2021 ◽

Author(s):

Hema Saranya Ilamathi ◽

Sara Benhammouda ◽

Justine Desrochers-Goyette ◽

Matthew A Lines ◽

Marc Germain

Keyword(s):

Endoplasmic Reticulum ◽

Mitochondrial Dna ◽

Protein Complexes ◽

Mitochondrial Dynamics ◽

Mitochondrial Fission ◽

Mitochondrial Diseases ◽

Contact Sites ◽

Transport Chain ◽

Essential Components ◽

Mtdna Replication

Mitochondria are multi-faceted organelles crucial for cellular homeostasis that contain their own genome. Mitochondrial DNA (mtDNA) codes for several essential components of the electron transport chain, and mtDNA maintenance defects lead to mitochondrial diseases. mtDNA replication occurs at endoplasmic reticulum (ER)-mitochondria contact sites and is regulated by mitochondrial dynamics. Specifically, mitochondrial fusion is essential for mtDNA maintenance. In contrast, while loss of mitochondrial fission causes the aggregation of nucleoids (mtDNA-protein complexes), its role in nucleoid distribution remains unclear. Here, we show that the mitochondrial fission protein DRP1 regulates nucleoid segregation by altering ER sheets, the ER structure associated with protein synthesis. Specifically, DRP1 loss or mutation leads to altered ER sheets that physically interact with mitobulbs, mitochondrial structures containing aggregated nucleoids. Importantly, nucleoid distribution and mtDNA replication were rescued by expressing the ER sheet protein CLIMP63. Thus, our work identifies a novel mechanism by which DRP1 regulates mtDNA replication and distribution.

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Extremely low-frequency pulses of faint magnetic field, weaker than the geomagnetic field, induce mitophagy to rejuvenate mitochondria

10.21203/rs.3.rs-528037/v1 ◽

2021 ◽

Author(s):

Takuro Toda ◽

Mikako Ito ◽

Jun-ichi Takeda ◽

Alkio Masuda ◽

Nobutaka Hattori ◽

...

Keyword(s):

Magnetic Fields ◽

Geomagnetic Field ◽

Low Frequency ◽

Mitochondrial Mass ◽

Complex Ii ◽

Extremely Low Frequency ◽

Mitochondrial Homeostasis ◽

Weak Magnetic Fields ◽

Transport Chain ◽

Chemical Inhibition

Abstract Humans are frequently exposed to time-varying and static weak magnetic fields (WMF). However, the effects of faint magnetic fields, weaker than the geomagnetic field, have not been reported. We found that extremely low-frequency (ELF)-WMF, comprised of serial pulses of 10 µT intensity at 1–8 Hz, which was three or more times weaker than the geomagnetic field, reduced mitochondrial mass to 70% and the mitochondrial electron transport chain (ETC) complex II activity to 88%. Chemical inhibition of electron flux through the mitochondrial ETC complex II nullified the effect of ELF-WMF. Suppression of ETC complex II subsequently induced mitophagy by translocating parkin and PINK1 to the mitochondria and by recruiting LC3-II. Thereafter, mitophagy induced PGC-1α-mediated mitochondrial biogenesis to rejuvenate mitochondria. The lack of PINK1 negated the effect of ELF-WMF. Thus, ELF-WMF may be applicable for the treatment of human diseases that exhibit compromised mitochondrial homeostasis, such as Parkinson’s disease.

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