Two NAD-linked redox shuttles maintain the peroxisomal redox balance in Saccharomyces cerevisiae

Al-Saryi, Nadal; Al-Hejjaj, Murtakab Y; Roermund, C. W. T. van; Hulmes, Georgia E.; Ekal, Lakhan; Payton, Chantell; Wanders, Ronald J. A.; Hettema, Ewald H.

doi:10.1038/s41598-017-11942-2

Cited by 35 publications

(39 citation statements)

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“…Conversely, NAD+ is likely shuttled into peroxisomes by SLC25A17 in mammalian cells 25 . A related pathway can use the yeast peroxisomal matrix protein Mdh3p, which converts oxaloacetate to malate through the oxidation of NADH 26 , a reaction that is critical for the maintenance of the peroxisomal redox balance 27 . In mammalian cells, a similar shuttle system uses a peroxisomal lactate dehydrogenase that converts pyruvate to lactate, where SLC16A1 shuttles pyruvate in and lactate out 28 .…”

Section: Introductionmentioning

confidence: 99%

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

2018

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Many cellular redox reactions housed within mitochondria, peroxisomes and the endoplasmic reticulum (ER) generate hydrogen peroxide (H2O2) and other reactive oxygen species (ROS). The contribution of each organelle to the total cellular ROS production is considerable, but varies between cell types and also over time. Redox-regulatory enzymes are thought to assemble at a “redox triangle” formed by mitochondria, peroxisomes and the ER, assembling “redoxosomes” that sense ROS accumulations and redox imbalances. The redoxosome enzymes use ROS, potentially toxic by-products made by some redoxosome members themselves, to transmit inter-compartmental signals via chemical modifications of downstream proteins and lipids. Interestingly, important components of the redoxosome are ER chaperones and oxidoreductases, identifying ER oxidative protein folding as a key ROS producer and controller of the tri-organellar membrane contact sites (MCS) formed at the redox triangle. At these MCS, ROS accumulations could directly facilitate inter-organellar signal transmission, using ROS transporters. In addition, ROS influence the flux of Ca2+ ions, since many Ca2+ handling proteins, including inositol 1,4,5 trisphosphate receptors (IP3Rs), SERCA pumps or regulators of the mitochondrial Ca2+ uniporter (MCU) are redox-sensitive. Fine-tuning of these redox and ion signaling pathways might be difficult in older organisms, suggesting a dysfunctional redox triangle may accompany the aging process.

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Section: Introductionmentioning

confidence: 99%

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

2018

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“…Fatty acid oxidation requires plenty of NAD + as a coenzyme which is continually supplied by Mdh3p and Gpd1p activity in peroxisomes (Figure 1a). Mdh3p is malate dehydrogenase localizing in peroxisomes and Gpd1p is glycerol 3-phosphate dehydrogenase localizing in both cytosolic and peroxisomal compartments [28]. The substrate for Mdh3p is oxaloacetate derived from aspartate transamination which is replenished by Agc1p activity (Figure 1a).…”

Section: Deletion Of Agc1 Inhibits Fat Utilization In the Stationary mentioning

confidence: 99%

“…PEX34 and PEX11 function in peroxisome proliferation [16]. In contrast, PEX5 functions in the import of peroxisome matrix proteins, such as Mdh3p, which is important for NAD + regeneration in peroxisomes [16,28].…”

Section: Over-expression Of Pex34 Mdh3 Gpd1 Increases the Longevitymentioning

confidence: 99%

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Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency

et al. 2020

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Citrin is a liver-specific mitochondrial aspartate–glutamate carrier encoded by SLC25A13. Citrin deficiency caused by SLC25A13 mutation results in carbohydrate toxicity, citrullinemia type II, and fatty liver diseases, the mechanisms of some of which remain unknown. Citrin shows a functional homolog in yeast aspartate-glutamate carrier (Agc1p) and agc1Δ yeasts are used as a model organism of citrin deficiency. Here, we found that agc1Δ yeasts decreased fat utilization, impaired NADH balance in peroxisomes, and decreased chronological lifespan. The activation of GPD1-mediated NAD+ regeneration in peroxisomes by GPD1 over-expression or activation of the malate–oxaloacetate NADH peroxisomal shuttle, by increasing flux in this NADH shuttle and over-expression of MDH3, resulted in lifespan extension of agc1Δ yeasts. In addition, over-expression of PEX34 restored longevity of agc1Δ yeasts as well as wild-type cells. The effect of PEX34-mediated longevity required the presence of the GPD1-mediated NADH peroxisomal shuttle, which was independent of the presence of the peroxisomal malate–oxaloacetate NADH shuttle and PEX34-induced peroxisome proliferation. These data confirm that impaired NAD+ regeneration in peroxisomes is a key defect in the yeast model of citrin deficiency, and enhancing peroxisome function or inducing NAD+ regeneration in peroxisomes is suggested for further study in patients’ hepatocytes.

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“…Furthermore, we observed that most PMP-tFT fusions in cells grown on oleate-plus plates displayed lower ratios on day three and four compared to days one and two ( Figure 2B). S cerevisiae cells grown on oleate-plus liquid medium reach stationary phase after approximately 24 hrs (Kawalek et al, 2016) compared to growth on oleate liquid medium, where the cells require around 64 hrs (~2.5 days) to reach stationary phase (Al-Saryi et al, 2017). While it is challenging to determine the growth phase of cells growing on plates, we suspect that cells expressing PMP-tFT fusions would be in the later stages of growth after three or four days on oleate-plus plates.…”

Section: The Stability Of Tft Tagged Proteins Vary Ranging From Unstmentioning

confidence: 98%

Peroxisomal membrane protein degradation in yeast

Devarajan¹

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The knowns and unknowns of peroxisomal membrane protein degradation Chapter 1 18 The knowns and unknowns of Peroxisomal membrane protein degradation 21 1 Often, E2 enzymes directly transfer Ub to a target protein, typically with the help of E3s such as really interesting new gene (RING) domain containing ligases, also called as RING E3s (Figure 1, point 1) (Ozkan et al., 2005). However in some cases, the Ub is first transferred from the E2 to the active site of a specific class of E3 (Figure 1, point 2), which possess homologous to the E6-AP carboxyl terminus (HECT) domain and these HECT E3s are responsible for attaching Ub to the lysine residue of the target protein (Metzger et al., 2012; Petroski et al., 2006). A third class of E3 ligase, distinct from the RING and HECT classes, are referred to as RING-in-between-RING (RBR) E3s (Figure 1, point 3) and they often contain a RING domain, followed by an RBR domain and finally a RING-like domain. These RBR E3s recruit an E2, which transfers ubiquitin to a cysteine in the RING-like domain before transferring to the substrate (Figure 1, point 3) (Wenzel et al., 2011). Figure 1: Schematic overview of the enzyme cascade catalyzing protein ubiquitination and degradation. Ubiquitin (Ub) is first activated by a ubiquitin activating enzyme (E1) with ATP hydrolysis. Next, the E1 transfers the Ub to a ubiquitin conjugating enzyme (E2), which is eventually transferred to a substrate with the aid of a ubiquitin ligase (E3). (1) RING-E3 serve as a bridge to enable Ub to be passed directly from the E2 to the substrate while (2) HECT-E3s accept Ub from the E2 onto their own active site before attaching it to a substrate. Chapter 1 22 RBR-E3 ligases (3) bind a Ub conjugated E2 and Ub is transferred from the E2 to the E3, after which Ub is then transferred to the substrate. Substrate proteins with single Ub can undergo several rounds of Ub chain elongation. Poly-ubiquitinated substrates are then targeted to the proteasome for degradation. Cells possess one or two E1s, several E2s (~11 in yeast and ~37 in humans) and multiple E3s (~50 E3s in yeast and ~1000/thousand in humans) (

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Two NAD-linked redox shuttles maintain the peroxisomal redox balance in Saccharomyces cerevisiae

Cited by 35 publications

References 36 publications

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages

Genetic Analysis of Peroxisomal Genes Required for Longevity in a Yeast Model of Citrin Deficiency

Peroxisomal membrane protein degradation in yeast

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