Monocarboxylate Transporter 1 (MCT1) Mediates Succinate Export in the Retina

Bisbach, Celia M; Hass, Daniel T.; Thomas, Eric D.; Cherry, Timothy J.; Hurley, James B.

doi:10.1167/iovs.63.4.1

Cited by 15 publications

(9 citation statements)

References 46 publications

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“…This transport is proton linked and is driven by changes in proton concentration (Halestrap & Price, 1999). Moreover, previous studies of muscle, heart, and recombinant protein have shown that MCT1 can transport succinate in its monocarboxylate form (Andrienko et al, 2017; Bisbach et al, 2022; Prag et al, 2021; Reddy et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Here we show that brown adipocyte uptake of succinate depends on the proportion of it in the monocarboxylic form, and relies substantially on MCT family proteins, in particular MCT1. It is noteworthy that a mechanism through which succinate is acquired by brown adipocytes appears to be an inversion of the succinate export mechanism recently discovered in a variety of cell types (Bisbach et al, 2022; Prag et al, 2021; Reddy et al, 2020).…”

Section: Discussionmentioning

confidence: 98%

“…Additionally, accumulated succinate is now well appreciated to regulate physiology through its secretion and ligation of the G-protein coupled receptor, succinate receptor 1 (SUCNR1)(Aguiar et al, 2014; Gilissen et al, 2016; McCreath et al, 2015; Mills et al, 2021; Reddy et al, 2020; Sadagopan et al, 2007; van Diepen et al, 2017). Recent studies have shown that succinate is selectively released from cells via the plasma membrane monocarboxylate transporter (MCT) 1 (Andrienko et al, 2017; Bisbach et al, 2022; Prag et al, 2021; Reddy et al, 2020). This process is initiated by intracellular acidification, for example in response to acute metabolic perturbations such as muscle exercise or tissue hypoxia (Prag et al, 2021; Reddy et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

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Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Reddy

Winther

Tran

et al. 2023

Preprint

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Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole body energy expenditure, counteracts obesity, and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion of it present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import, however other members of the MCT family can partially compensate and fulfill this role in the absence of MCT1. In mice, we show that acute pharmacological inhibition of MCT1 and 2 decreases succinate uptake into BAT. Conversely, congenital genetic depletion of MCT1 alone has little effect on BAT succinate uptake, indicative of additional transport mechanisms with high capacityin vivo. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Reddy

Winther

Tran

et al. 2023

Preprint

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“…Consistently, Female mice show more severe RPE damage and reduced retinal thickness under oxidative damage induced by sodium iodate 63, 64 . RPE mitochondria prefer to oxidize succinate from the retina to produce malate and fumarate for the retina 65-67 . However, succinate is lower in female RPE under both fed and fasted states.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific sex difference in mouse eye and brain metabolome under fed and fasted states

Saravanan

Roby

et al. 2023

Preprint

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Purpose: Visual physiology and various ocular diseases demonstrate sexual dimorphisms; however, how sex influences metabolism in different eye tissues remains undetermined. This study aims to address common and tissue-specific sex differences in metabolism in the retina, retinal pigment epithelium (RPE), lens and brain under fed and fasted conditions. Methods: After ad libitum fed or deprived of food for 18 hours, mouse eye tissues (retina, RPE/choroid, and lens), brain, and plasma were harvested for targeted metabolomics. The data were analyzed with both Partial least squares-discriminant analysis (PLS-DA) and Volcano Plot analysis. Results: Among 133 metabolites that cover major metabolic pathways, we found 9-45 metabolites that are sex-different in different tissues under the fed state and 6-18 metabolites under the fasted state. Among these sex-different metabolites, 33 were changed in two or more tissues, and 64 were tissue-specific. Pantothenic acid, hypotaurine and 4-hydroxyproline were the top commonly changed metabolites. Lens and retina had the most tissue-specific sex-different metabolites enriched in the metabolism of amino acid, nucleotide, lipids and TCA cycle. Lens and brain had more similar sex-different metabolites than other occular tissues. Female RPE and female brain were more sensitive to fasting with more reduced metabolites in amino acid metabolism, TCA cycle and glycolysis. The plasma had the least sex-different metabolites with very few overlapping changes with tissues. Conclusion: Sex has a strong influence on eye and brain metabolism in tissue-specific and metabolic state-specific manners. Our findings may implicate the sexual dimorphisms in eye physiology and susceptibility to ocular diseases.

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“…The normal fuel preferences for this tissue are not known, but likely include lactate and succinate. Those metabolites are released by retina tissue explants and consumed by RPE-choroid explants (7,8,11,13,15,16). As we had done with glucose, we determined the contribution of alternate fuels to tissue metabolism in vivo, using jugular vein infusions of 13 C 3 -lactate (Fig.…”

Section: S1d)mentioning

confidence: 99%

In vivoexchange of glucose and lactate between photoreceptors and the retinal pigment epithelium

Hass

Giering²,

Bisbach

et al. 2023

Preprint

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The posterior eye contains two metabolic microenvironments, each occupied by a distinct tissue type. Retinal pigment epithelium (RPE)-choroid tissue is connected to the circulatory system and receives plentiful O2and nutrients. Tight junctions formed by the RPE regulate the diffusion of nutrients to the neural retina. Retina tissue consequently exists in an environment with low O2levels and a lower variety of fuels that can support its metabolic needs. Retina explants release lactate and succinate, presumably as an adaptation to a low O2environment where they cannot be fully oxidized. The RPE-choroid is thought to aid retina metabolism by oxidizing these ′waste′ products. We tested these ideas in vivo by infusing13C-labeled fuels through jugular vein catheters into circulation. By probing the patterns of13C labeling in glycolysis and the TCA cycle from different fuels and genetic models, we found that the retina and RPE do form a cooperative metabolic relationship, where the RPE-choroid oxidizes retina derived succinate but not lactate. Rather than consuming lactate, mouse RPE-choroid may act as a conduit for retina-derived lactate to re-enter circulation and feed more distant tissues.

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Monocarboxylate Transporter 1 (MCT1) Mediates Succinate Export in the Retina

Cited by 15 publications

References 46 publications

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes

Tissue-specific sex difference in mouse eye and brain metabolome under fed and fasted states

In vivoexchange of glucose and lactate between photoreceptors and the retinal pigment epithelium

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