UPRmt and coordinated UPRER in type 2 diabetes

Kang, Zhaofeng; Chen, Feng; Wu, Wanhui; Li, Rui; Chen, Tianda; Xu, Fang

doi:10.3389/fcell.2022.974083

Cited by 14 publications

(12 citation statements)

References 173 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consequently, we propose that proximal tubulopathy is likely the dominant phenotype of GRP170 depleted mice because the PT is highly dependent on aerobic metabolism and poorly perfused, even under ideal circumstances (14). Hence, the PT is especially vulnerable to oxygen debt or other cell stressors, such as the UPR and ER stress, which can also compromise mitochondrial function and impair ATP generation (53,(73)(74)(75).…”

Section: Discussionmentioning

confidence: 99%

Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron

Porter,

Vorndran,

Marciszyn

et al. 2024

Preprint

View full text Add to dashboard Cite

The maintenance of fluid and electrolyte homeostasis by the kidney requires proper folding and trafficking of ion channels and transporters in kidney epithelia. Each of these processes requires a specific subset of a diverse class of proteins termed molecular chaperones. One such chaperone is GRP170, which is an Hsp70-like, endoplasmic reticulum (ER)-localized chaperone that plays roles in protein quality control and protein folding in the ER. We previously determined that loss of GRP170 in the mouse nephron leads to hypovolemia, electrolyte imbalance, and rapid weight loss. In addition, GRP170-deficient mice develop an AKI-like phenotype, typified by tubular injury, elevation of clinical kidney injury markers, and induction of the unfolded protein response (UPR). By using an inducible GRP170 knockout cellular model, we confirmed that GRP170 depletion induces the UPR, triggers an apoptotic response, and disrupts protein homeostasis. Based on these data, we hypothesized that UPR induction underlies hyponatremia and volume depletion in rodents, but that these and other phenotypes might be rectified by supplementation with high salt. To test this hypothesis, control and GRP170 tubule-specific knockout mice were provided with a diet containing 8% sodium chloride. We discovered that sodium supplementation improved electrolyte imbalance and reduced clinical kidney injury markers, but was unable to restore weight or tubule integrity. These results are consistent with UPR induction contributing to the kidney injury phenotype in the nephron-specific GR170 knockout model, and that the role of GRP170 in kidney epithelia is essential to both maintain electrolyte balance and cellular protein homeostasis.

show abstract

Section: Discussionmentioning

confidence: 99%

Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron

Porter,

Vorndran,

Marciszyn

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…UPR mt is a mitochondrial stress response that is proposed to be induced by imbalanced protein synthesis between mitochondrion and nucleus, which in turns controls gene expression in the nucleus to balance the protein homeostasis 14 , 22 . Impaired UPR mt has recently been shown to be important for a variety of disease including cancer and neurodegenerative diseases, but its role in IGT and T2D remains unclear 17 , 39 . Interestingly, however, the current paradigm proposes UPR mt as a rescue response which plays a beneficial role in preventing disease and extending lifespan.…”

Section: Discussionmentioning

confidence: 99%

MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response

Lin,

Yu,

Lin

et al. 2023

Sci Rep

View full text Add to dashboard Cite

Lack of efficient insulin secretion from the pancreas can lead to impaired glucose tolerance (IGT), prediabetes, and diabetes. We have previously identified two IGT-associated single nucleotide polymorphisms (SNPs) rs62212118 and rs13052524 located at two overlapping genes: MRPS6 and SLC5A3. In this study, we show that MRPS6 but not SLC5A3 regulates glucose-stimulated insulin secretion (GSIS) in primary human β-cell and a mouse pancreatic insulinoma β-cell line. Data mining and biochemical studies reveal that MRPS6 is positively regulated by the mitochondrial unfolded protein response (UPRmt), but feedback inhibits UPRmt. Disruption of such feedback by MRPS6 knockdown causes UPRmt hyperactivation in high glucose conditions, hence elevated ROS levels, increased apoptosis, and impaired GSIS. Conversely, MRPS6 overexpression reduces UPRmt, mitigates high glucose-induced ROS levels and apoptosis, and enhances GSIS in an ATF5-dependent manner. Consistently, UPRmt up-regulation or down-regulation by modulating ATF5 expression is sufficient to decrease or increase GSIS. The negative role of UPRmt in GSIS is further supported by analysis of public transcriptomic data from murine islets. In all, our studies identify MRPS6 and UPRmt as novel modulators of GSIS and apoptosis in β-cells, contributing to our understanding of the molecular and cellular mechanisms of IGT, prediabetes, and diabetes.

show abstract

“…Mouse embryonic fibroblasts with PERK knocked out, have a disrupted MERCS network, altered ER morphology, disrupted redox signalling and impaired Ca 2+ transport [215,216]. PERK is a regulatory signalling hub that monitors stress in both organelles and its Cys216 can be reversibly oxidised allowing formation of covalent interactions with ERO1α and tightening of MERCS [90,217]. UPR ER and UPR mt establish a crosstalk in response to proteotoxic stress through PERK activation, regulating the coactivation of CHOP and ATF4 and increasing the expression of ATF5, promoting the translation of ER and mitochondrial chaperones to alleviate proteotoxic stress [217].…”

Section: Redox Regulation Of Mercsmentioning

confidence: 99%

“…PERK is a regulatory signalling hub that monitors stress in both organelles and its Cys216 can be reversibly oxidised allowing formation of covalent interactions with ERO1α and tightening of MERCS [90,217]. UPR ER and UPR mt establish a crosstalk in response to proteotoxic stress through PERK activation, regulating the coactivation of CHOP and ATF4 and increasing the expression of ATF5, promoting the translation of ER and mitochondrial chaperones to alleviate proteotoxic stress [217]. As mentioned, the UPR can be an adaptive or maladaptive response depending on stress intensity and duration, that can impact mitochondrial morphology and function [172,218,219].…”

Section: Redox Regulation Of Mercsmentioning

confidence: 99%

Redox regulation of UPR signalling and mitochondrial ER contact sites

Casas-Martinez,

Samali,

McDonagh

2024

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Mitochondria and the endoplasmic reticulum (ER) have a synergistic relationship and are key regulatory hubs in maintaining cell homeostasis. Communication between these organelles is mediated by mitochondria ER contact sites (MERCS), allowing the exchange of material and information, modulating calcium homeostasis, redox signalling, lipid transfer and the regulation of mitochondrial dynamics. MERCS are dynamic structures that allow cells to respond to changes in the intracellular environment under normal homeostatic conditions, while their assembly/disassembly are affected by pathophysiological conditions such as ageing and disease. Disruption of protein folding in the ER lumen can activate the Unfolded Protein Response (UPR), promoting the remodelling of ER membranes and MERCS formation. The UPR stress receptor kinases PERK and IRE1, are located at or close to MERCS. UPR signalling can be adaptive or maladaptive, depending on whether the disruption in protein folding or ER stress is transient or sustained. Adaptive UPR signalling via MERCS can increase mitochondrial calcium import, metabolism and dynamics, while maladaptive UPR signalling can result in excessive calcium import and activation of apoptotic pathways. Targeting UPR signalling and the assembly of MERCS is an attractive therapeutic approach for a range of age-related conditions such as neurodegeneration and sarcopenia. This review highlights the emerging evidence related to the role of redox mediated UPR activation in orchestrating inter-organelle communication between the ER and mitochondria, and ultimately the determination of cell function and fate.

show abstract

UPRmt and coordinated UPRER in type 2 diabetes

Cited by 14 publications

References 173 publications

Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron

Excess dietary sodium partially restores salt and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron

MRPS6 modulates glucose-stimulated insulin secretion in mouse islet cells through mitochondrial unfolded protein response

Redox regulation of UPR signalling and mitochondrial ER contact sites

Contact Info

Product

Resources

About