Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Gansemer, Erica R.; Rutkowski, D. Thomas

doi:10.3389/fmolb.2022.858142

Cited by 4 publications

(1 citation statement)

References 213 publications

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“…Communication between the ER and mitochondria is tightly regulated by mitochondria associated membranes ( Zhang et al, 2021 ). ER homeostasis drives biosynthetic pathways including lipogenesis and gluconeogenesis ( Gansemer and Rutkowski, 2022 ). The ER is composed of a set of membranes or cisternae that are held together by the cytoskeleton.…”

Section: Organelles Targeted By Age-associated Energy Deficienciesmentioning

confidence: 99%

Using mass spectrometry imaging to visualize age-related subcellular disruption

Hogan

Zeidler²,

Beasley³

et al. 2023

Front. Mol. Biosci.

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Metabolic homeostasis balances the production and consumption of energetic molecules to maintain active, healthy cells. Cellular stress, which disrupts metabolism and leads to the loss of cellular homeostasis, is important in age-related diseases. We focus here on the role of organelle dysfunction in age-related diseases, including the roles of energy deficiencies, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, changes in metabolic flux in aging (e.g., Ca2+ and nicotinamide adenine dinucleotide), and alterations in the endoplasmic reticulum-mitochondria contact sites that regulate the trafficking of metabolites. Tools for single-cell resolution of metabolite pools and metabolic flux in animal models of aging and age-related diseases are urgently needed. High-resolution mass spectrometry imaging (MSI) provides a revolutionary approach for capturing the metabolic states of individual cells and cellular interactions without the dissociation of tissues. mass spectrometry imaging can be a powerful tool to elucidate the role of stress-induced cellular dysfunction in aging.

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Section: Organelles Targeted By Age-associated Energy Deficienciesmentioning

confidence: 99%

Using mass spectrometry imaging to visualize age-related subcellular disruption

Hogan

Zeidler²,

Beasley³

et al. 2023

Front. Mol. Biosci.

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An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice

Mattocks,

Ommi,

Malloy

et al. 2024

GeroScience

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Protein folding in the endoplasmic reticulum (ER) requires a high ratio of oxidized to reduced glutathione (GSSG/rGSH). Since the GSSG/rGSH depends on total glutathione (tGSH = GSSG + rGSH) levels, we hypothesized that limiting GSH biosynthesis will ameliorate protein misfolding by enhancing the ER oxidative milieu. As a proof-of-concept, we used DL-buthionine-(S,R)-sulfoximine (BSO) to inhibit GSH biosynthesis in Akita mice, which are prone to proinsulin misfolding. We conducted a 2-week intervention to investigate if BSO was safe and a 6-week intervention to find its effect on glucose intolerance. In both cohorts, male heterozygous Akita (AK) and wild-type (WT) mice were continuously administered 15 mM BSO. No adverse effects were observed on body weight, food intake, and water intake in either cohort. Unaltered levels of plasma aspartate and alanine aminotransferases, and cystatin-C, indicate that BSO was safe. BSO-induced decreases in tGSH were tissue-dependent with maximal effects in the kidneys, where it altered the expression of genes associated with GSH biosynthesis, redox status, and proteostasis. BSO treatment decreased random blood glucose levels to 80% and 67% of levels in untreated mice in short-term and long-term cohorts, respectively, and 6-h fasting blood glucose to 82% and 74% of levels in untreated mice, respectively. BSO also improved glucose tolerance by 37% in AK mice in the long-term cohort, without affecting insulin tolerance. Neither glucose tolerance nor insulin tolerance were affected in WT. Data indicate that BSO might treat misfolded proinsulin-induced glucose intolerance. Future studies should investigate the effect of BSO on proinsulin misfolding and if it improves glucose intolerance in individuals with Mutant Insulin Diabetes of Youth. Graphical abstract 1) Male heterozygous C57BL/6-Ins2Akita/J (AK) mice suffer from misfolded proinsulin-induced glucose intolerance. (a) Proinsulin misfolding occurs due to a genetic mutation in Ins2 gene that substitutes Cys with Tyr, (b) Due to heterozygosity, AK mice produce both wild-type and mutated proinsulin, (c) Mutated proinsulin forms aggregates with itself and with the bystander native proinsulin, (d) Proinsulin aggregation results in lower functional insulin, and (e) AK mice suffer from impaired glucose tolerance. 2) Treating mice with BSO improved glucose tolerance. (a) Mice were treated with continuous administration of 15 mM DL -buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione biosynthesis (b), BSO treatment increased the renal mRNA quantity of several genes involved in glutathione biosynthesis, glutathione redox status, and proteostasis, (c) we hypothesize that BSO-induced changes in cellular redox status and gene expression ameliorates proinsulin aggregation and increases the functional insulin levels in β-cells, and (d) BSO treatment significantly improved glucose intolerance in AK mice. Note: AUC - Area under the curve, GCL -γ-g-glutamylcysteine ligase, GS - Gluatthione synthetase.

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Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation

Morelli,

Scholkmann

2024

Biochimie

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Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress

Cited by 4 publications

References 213 publications

Using mass spectrometry imaging to visualize age-related subcellular disruption

Using mass spectrometry imaging to visualize age-related subcellular disruption

An antireductant approach ameliorates misfolded proinsulin-induced hyperglycemia and glucose intolerance in male Akita mice

Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation

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