Obligatory role of endoplasmic reticulum in brain FDG uptake

Cossu, Vanessa; Marini, Cecilia; Piccioli, Patrizia; Rocchi, Anna; Bruno, Silvia; Orengo, Anna Maria; Emionite, Laura; Bauckneht, Matteo; Grillo, Federica; Capitanio, Selene; Balza, Enrica; Yosifov, Nikola; Castellani, Patrizia; Caviglia, Giacomo; Panfoli, Isabella; Morbelli, Silvia; Ravera, Silvia; Benfenati, Fabio; Sambuceti, Gianmario

doi:10.1007/s00259-018-4254-2

Cited by 31 publications

(63 citation statements)

References 32 publications

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“…Quadriceps muscle side was randomly selected. Ex vivo FDG uptake of quadriceps and hearts was evaluated using the Ligand-Tracer White ® instrument (Ridgeview, Uppsala, SE) according to our previously validated procedure [12,14,19]. Brie y, the device consists of a betaemission detector and a rotating platform harboring a standard Petri dish.…”

Section: Ex Vivo Extraction Fraction Of Fdg and Glucosementioning

confidence: 99%

“…Slices (300 µm thick) of quadriceps or hearts were stuck in the outer ring of a Petri dish with octyl-cyanoacrylate (Dermabond, Ethicon, US) and covered with 3 mL solution collected from an input vial containing 4 mL of Dulbecco's Modi ed Eagle's Medium (DMEM) containing glucose and FDG at the concentration of 5.5 mM (1 g/L) and 2 MBq/mL, respectively. Time-activity curves were thus obtained by subtracting decay-corrected background counting rate from the corresponding target value, as previously described [12,14,[19][20]. After 40 min, an aliquot of 0.5 mL was sampled both from the input vial and from the Petri dish (output) to measure the radioactivity concentration using a dose calibrator with an activity resolution <10 KBq (Capintec CRC55).…”

Section: Ex Vivo Extraction Fraction Of Fdg and Glucosementioning

confidence: 99%

“…To assess lipid peroxidation, malondialdehyde (MDA) levels were evaluated, by the thiobarbituric acid reactive substances (TBARS) assay, with minor modi cations [13,25]. The activity assay of the Complex I was measured on 50μg of total protein as previously described [10,12,26].…”

Section: Enzymatic Assaymentioning

confidence: 99%

“…FDG uptake is commonly considered an index of glucose consumption. Nevertheless, several studies recently challenged this classical assumption and reported a direct and strict link between tracer retention and the activation of a speci c pentose phosphate pathway (PPP) triggered by the "omnivore" enzyme hexose-6P-dehydrogenase (H6PD) within the endoplasmic reticulum (ER) of cancer cells [10][11], neurons and astrocytes [12], cardiomyocytes [13] and, more importantly, in skeletal muscles [14]. A major function of PPP is the reduction of NADP + to NADPH to fuel the glutathione-dependent antioxidant responses.…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

Marini

Cossu

Bonifacino

et al. 2020

Preprint

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Background. We recently reported that enhanced [18F]-fluorodeoxyglucose (FDG) uptake in skeletal muscles predicts disease aggressiveness in patients with amyotrophic lateral sclerosis (ALS). The present experimental study aimed to assess whether this predictive potential reflects the link between FDG uptake and redox stress that has been previously reported in different tissues and disease models. Methods. The study included 15 SOD1G93A mice (as experimental ALS model) and 15 wildtype mice (around 120-days-old). Mice were submitted to micro-PET imaging. Enzymatic pathways and response to oxidative stress were evaluated in harvested quadriceps and hearts by biochemical, immunohistochemical and immunofluorescence analysis. Colocalization between the endoplasmic reticulum (ER) and the fluorescent FDG analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) was performed in fresh skeletal muscle sections. Finally, mitochondrial ultrastructure and bioenergetics were evaluated in harvested quadriceps and hearts.Results. FDG retention was significantly higher in hindlimb skeletal muscles of symptomatic SOD1G93A mice with respect to control ones. This difference was not explained by any acceleration in glucose degradation through glycolysis or cytosolic pentose phosphate pathway (PPP). Similarly, it was independent of inflammatory infiltration. Rather, the high FDG retention in SOD1G93A skeletal muscle was associated with an accelerated generation of reactive oxygen species. This redox stress selectively involved the ER and the local PPP triggered by hexose-6P-dehydrogenase. ER involvement was confirmed by the colocalization of the 2-NBDG with a vital ER tracker. The oxidative damage in transgenic skeletal muscle was associated with a severe impairment in the crosstalk between ER and mitochondria combined with alterations in mitochondrial ultrastructure and fusion/fission balance. The expected respiratory damage was confirmed by a deceleration in ATP synthesis and oxygen consumption rate. These same abnormalities were represented to a markedly lower degree in the myocardium, as a sample of non-voluntary striated muscle.Conclusion. Skeletal muscle of SOD1G93A mice reproduces the increased FDG uptake observed in ALS patients. This finding reflects the selective activation of the ER-PPP in response to significant redox stress associated with alterations of mitochondrial ultrastructure, networking, and connection with the ER itself. This scenario is less severe in cardiomyocytes suggesting a relevant role for either communication with synaptic plaque or contraction dynamics.

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Section: Ex Vivo Extraction Fraction Of Fdg and Glucosementioning

confidence: 99%

Section: Ex Vivo Extraction Fraction Of Fdg and Glucosementioning

confidence: 99%

Section: Enzymatic Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mechanisms underlying the predictive power of high skeletal muscle uptake of FDG in Amyotrophic Lateral Sclerosis

Marini

Cossu

Bonifacino

et al. 2020

Preprint

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“…[27]), some of which were found biochemically active [28][29][30] . On the other hand, it is reasonable believe that a mechanism as the extramitochondrial aerobic metabolism may not be exclusive of the nervous system, but exploited when a considerable amount of ATP is needed, such as in cancer cells [28,31] . Moreover, the exportability of mitochondrial proteins is suggested by the strictly interaction and membrane trafficking between mitochondria and the other cellular membranous structure, i.e., ER [32] .…”

Section: New Perspectives On Oxidative Metabolism In Plateletsmentioning

confidence: 99%

Platelet aerobic metabolism: new perspectives

Ravera¹,

Panfoli²

2019

JUMD

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Although the role of platelets in hemostasis and thrombotic disorders as well as their contribution to inflammation are known, recent studies support the notion that much remains to be learned about platelet bioenergetics. Recent data suggest that platelets possess extra-mitochondrial oxidative phosphorylation (OXPHOS), which could represent one of sources of the chemical energy necessary for the prompt platelets activation. However, the extra-mitochondrial OXPHOS can play both beneficial and pathological roles, since the OXPHOS is the principal responsible of oxidative stress generation. For this reason, several authors evaluated the effects of polyphenols and other antioxidants on the modulation of the platelets oxidative stress production. In conclusion, we believe that a better understanding of platelet oxidative metabolism would allow a deeper knowledge of their physiology and the designing novel treatments targeting the role of platelets in many human diseases.

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