Loss of MPC1 reprograms retinal metabolism to impair visual function

Grenell, Allison; Wang, Yekai; Yam, Michelle; Swarup, Aditi; Dilan, Tanya L.; Hauer, Allison; Linton, Jonathan D.; Philp, Nancy J.; Gregor, Elizabeth; Zhu, Siyan; Shi, Quan; Murphy, Joseph; Guan, Tongju; Lohner, Daniel; Kolandaivelu, Saravanan; Ramamurthy, Visvanathan; Goldberg, Andrew F.X.; Hurley, James B.; Du, Jianhai

doi:10.1073/pnas.1812941116

Cited by 83 publications

(114 citation statements)

References 38 publications

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“…Thus, it is not surprising that deranged pyruvate metabolism contributes to a host of diseases (6). Since the molecular identification of the genes encoding the MPC (7,9), an increasing number of investigations have demonstrated the prominent role of mitochondrial pyruvate uptake in regulating cellular and organismal biology (11,12,15,23,(25)(26)(27). Here, we demonstrate that 2 MPC1 mutations identified in human patients with inborn errors in pyruvate metabolism cause MPC dysfunction by three different mechanisms.…”

Section: Discussionmentioning

confidence: 70%

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Oonthonpan¹,

Rauckhorst²,

Gray³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 70%

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Oonthonpan¹,

Rauckhorst²,

Gray³

et al. 2019

JCI Insight

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“…Studies have also shown that glucose is essential for proper photoreceptor function, as deletion of GLUT1 in the RPE did not affect RPE function but led to photoreceptor cell death 41 . In addition to glycolysis, mitochondrial function is also essential for proper photoreceptor function, as deletion of the mitochondrial pyruvate carrier (MPC1) in the neuroretina results in retinal degeneration 42 . Several findings have also implicated metabolic dysregulation in the pathogenesis of AMD 43–45 .…”

Section: Discussionmentioning

confidence: 99%

AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

Brown

Keuthan

et al. 2020

Preprint

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15The retina has one of the highest energy demands in the human body, and proper 16 regulation of metabolism among the cell types of the retina is required for functional vision. 17Recent studies have reported that retinal metabolism is disrupted during retinal degeneration 18 and aging, while therapies designed to enhance metabolism can slow or prevent degeneration. 19Here, we show that multiple metabolic pathways, including those regulated by a key ATP sensor 20 and regulator of metabolism, AMP-activated-kinase (AMPK), were dysregulated in a model of 21 inherited retinal degeneration. In order to assess the direct role of AMPK in regulating retinal 22 metabolism, we used mice with retina-specific knockout of AMPK activity. Conditional loss of 23 AMPK resulted in impaired visual function at an early age, with slow photoreceptor loss 24 observed in older mice. Moreover, we found that loss of AMPK resulted in decreased metabolic 25 flux from glucose, decreased mitochondrial DNA copy number, decreased mitochondrial-related 26 gene expression, and alterations in mitochondrial morphology in the photoreceptors, all of which 27 preceded degeneration. Surprisingly, metabolic changes from the loss of AMPK in retinal 28 neurons also resulted in secondary degeneration of retinal pigment epithelial (RPE) cells. 29Together, these data show that AMPK signaling is important for maintaining metabolic 30 homeostasis of the retina and support the hypothesis that photoreceptors and RPE have a 31 shared metabolic ecosystem that is controlled, in part, by AMPK. 32 33 Main 34 The central nervous system, including the retina, is often cited as having one of the 35 highest energy demands in the body, with pathways that require utilization of ATP, glucose, 36 lactate, fatty acids, glutathione (GSH), and NADPH for proper neuronal function and protection 37 against retinal degeneration 1-4 . As much as half of the metabolites and metabolic activity in the 38 retina are located in the light-sensitive photoreceptors 5,6 . ATP is heavily consumed by NaK-39 ATPases in photoreceptors to maintain the ion gradient within the cells, and a considerable 40 amount of energy is dedicated to supporting phototransduction in response to light 1,2 . While 41 disruption of metabolism has been associated with retinal degeneration, manipulations that 42 restore energy homeostasis by enhancing glycolysis or mitochondrial activity can preserve 43 retinal function and promote photoreceptor survival 7-12 . 44 However, little is known about how metabolic activity is regulated in the retina. The 5' 45 adenosine monophosphate-activated protein kinase (AMPK) pathway is a logical control 46 mechanism for high metabolic activity in cells. AMPK is an evolutionarily conserved 47 EY016459, the Foundation Fighting Blindness, and an unrestricted grant from Research to 388 Prevent Blindness. The authors wish to acknowledge the contributions of Lena Phu for her 389 assistance in genotyping, qRT-PCR, and measuring ONL thicknesses. The authors also wish to 390 acknowledge the...

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“…Aspartate catabolism may 1) recycle NADH into NAD + to sustain the highly active glycolysis, 2) provide cytosolic electrons for ATP production, 3) replenish mitochondrial OAA for biosynthesis and 4) produce cytosolic and mitochondrial pyruvate through malic enzymes (Fig 6). Interestingly, low glucose or inhibition of glucose oxidation could cause massive accumulation of aspartate in the neural retina with severe depletion of glutamate 38,39,40 . Therefore, aspartate utilization supports active glycolysis, mitochondrial metabolism and glutamate synthesis.…”

Section: Discussionmentioning

confidence: 99%

“…Besides being a neurotransmitter, glutamate is an important substrate for the TCA cycle and the synthesis of glutamine and glutathione (Fig 6). Decreased glutamate availability substantially reduces the levels of glutamine and glutathione 39 . Glutamate also serves as a major nitrogen donor to synthesize non-essential amino acids by transaminases and is a precursor for GABA by decarboxylation (Fig 6).…”

Section: Discussionmentioning

confidence: 99%

“…The SLC16A3 (MCT4), which has low affinity for pyruvate in order to preserve intracellular pyruvate levels, 51 is strongly expressed in the neural macula ( Table S9). Inhibition of pyruvate utilization causes visual impairment in mice and fish due to photoreceptor degeneration 39,52 . Pyruvate provides metabolic advantages that enhance both glycolysis and mitochondrial metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

Zhang

Liu

et al. 2020

Preprint

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Photoreceptors, especially cones, which are enriched in the human macula, have high energy demands, making them vulnerable to metabolic stress. Metabolic dysfunction of photoreceptors and their supporting retinal pigment epithelium (RPE) is an important underlying cause of degenerative retinal diseases. However, how cones and the macula support their exorbitant metabolic demand and communicate with RPE is unclear. By profiling metabolite uptake and release and analyzing metabolic genes, we have found cone-rich retinas and human macula share specific metabolic features with upregulated pathways in pyruvate metabolism, mitochondrial TCA cycle and lipid synthesis. Human neural retina and RPE have distinct but complementary metabolic features. Retinal metabolism centers on NADH production and neurotransmitter biosynthesis. The retina needs aspartate to sustain its aerobic glycolysis and mitochondrial metabolism. RPE metabolism is directed toward NADPH production and biosynthesis of acetyl-rich metabolites, serine and others. RPE consumes multiple nutrients, including proline, to produce metabolites for the retina.

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Loss of MPC1 reprograms retinal metabolism to impair visual function

Cited by 83 publications

References 38 publications

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction

AMP-activated-protein kinase (AMPK) is an essential sensor and metabolic regulator of retinal neurons and their integrated metabolism with RPE

Metabolic features of mouse and human retinas: rods vs. cones, macula vs. periphery, retina vs. RPE

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