An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis

Birsoy, Kıvanç; Wang, Yichen; Chen, Walter W.; Freinkman, Elizaveta; Abu-Remaileh, Monther; Sabatini, David M.

doi:10.1016/j.cell.2015.07.016

Cited by 1,162 publications

(1,272 citation statements)

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“…Light also could inhibit de novo purine synthesis by decreasing the amount of aspartate in the cell. Recent studies showed that decreases in nucleotide levels correlate with reduced synthesis of aspartate (52)(53)(54)(55)(56). These are reasonable mechanisms by which light could regulate de novo purine synthesis.…”

Section: Illumination Influences Nucleotide Metabolismmentioning

confidence: 99%

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Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Rountree

Cleghorn³

et al. 2016

Journal of Biological Chemistry

100

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Production of energy in a cell must keep pace with demand.Photoreceptors use ATP to maintain ion gradients in darkness, whereas in light they use it to support phototransduction. Matching production with consumption can be accomplished by coupling production directly to consumption. Alternatively, production can be set by a signal that anticipates demand. In this report we investigate the hypothesis that signaling through phototransduction controls production of energy in mouse retinas. We found that respiration in mouse retinas is not coupled tightly to ATP consumption. By analyzing metabolic flux in mouse retinas, we also found that phototransduction slows metabolic flux through glycolysis and through intermediates of the citric acid cycle. We also evaluated the relative contributions of regulation of the activities of ␣-ketoglutarate dehydrogenase and the aspartate-glutamate carrier 1. In addition, a comprehensive analysis of the retinal metabolome showed that phototransduction also influences steady-state concentrations of 5-GMP, ribose-5-phosphate, ketone bodies, and purines. Warburg et al.(1) and Krebs (2) reported in the 1920s that tumors and retinas rely on aerobic glycolysis. Some of the biochemical mechanisms by which cancer cells adapt to aerobic glycolysis have been gleaned from investigations of specific metabolic adaptations of cancer cells either in culture or in a tumor (3, 4). Retinas offer distinct advantages for investigating aerobic glycolysis. They have high metabolic rates, a uniquely laminated structure, and the primary signaling pathway by which retinas respond to light is defined clearly.Retinas convert 80 -96% of glucose they consume into lactic acid (5-9), similar to the extent of aerobic glycolysis that fuels cancer cells (3). Aerobic glycolysis occurs primarily in photoreceptors (10) where the energy demands are very different in darkness than in light (5,7,(11)(12)(13). In darkness energy is consumed within the inner segments to support ion pumping (5, 13). In light energy is consumed by the outer segments (OS) 2 to support phototransduction and regeneration of visual pigments. A photoreceptor neuron also performs anabolic metabolism to replace the ϳ10% of its OS material that is lost each day to phagocytosis by the retinal pigmented epithelium (14, 15).Some of the carbons in glucose consumed by a retina reach the mitochondrial matrix where they are oxidized in biochemical reactions that reduce NAD ϩ to NADH. Transfer of electrons from NADH to O 2 then generates a proton gradient across the mitochondrial inner membrane. In some tissues dissipation of the proton gradient is coupled tightly to ATP demand. In others, proton leakage can dissipate the gradient even without ATP synthesis (16). In this report we show that mitochondria in retinas are more uncoupled than mitochondria in other tissues.The ability of a photoreceptor to respond to light, to release neurotransmitter, to regenerate visual pigment, to renew itself, and to remain viable requires that production of energy keeps pace...

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Section: Illumination Influences Nucleotide Metabolismmentioning

confidence: 99%

“…Recent studies of metabolism in other types of cells also concluded that anabolic activities of mitochondria can even be more essential than ATP synthesis (53,55).…”

Section: Control Of Metabolism By Signalingmentioning

confidence: 99%

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Rountree

Cleghorn³

et al. 2016

Journal of Biological Chemistry

100

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“…The importance for aspartate metabolite in addition to alpha-ketoglutarate for survival of HDAC5-depleted cells is quite interesting. The role of this amino acid and its interaction with glutamine/glutamate and TCA cycle metabolism is becoming more and more studied in cancer cells [33][34][35][36] and this should be also further addressed in the context of HDAC5 depletion.…”

Section: Discussionmentioning

confidence: 99%

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

et al. 2017

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The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.

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“…The TCA cycle could also be required during rapid growth, even when ATP production by OXPHOS is not necessary, to maintain synthesis of biomolecules such as glutamate or aspartate. A recent study has reported that an essential function of respiration in proliferating cells is to support aspartate synthesis [68,69]; minimal flow through the TCA cycle therefore needs to be maintained even when the ETC is repressed. Iron deficiency also leads to repression of transcripts encoding ETC subunits, but in this condition the succinate dehydrogenase complex is also strongly repressed [70,71] (Additional file 2: Figure S16).…”

Section: Discussionmentioning

confidence: 99%

Functional and Regulatory Profiling of Energy Metabolism in Fission Yeast

Małecki

Bitton

Rodríguez-López

et al. 2016

Preprint

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Background: The control of energy metabolism is fundamental for cell growth and function and anomalies in it are implicated in complex diseases and ageing. Metabolism in yeast cells can be manipulated by supplying different carbon sources: yeast grown on glucose rapidly proliferates by fermentation, analogous to tumour cells growing by aerobic glycolysis, whereas on non-fermentable carbon sources metabolism shifts towards respiration. Results: We screened deletion libraries of fission yeast to identify over 200 genes required for respiratory growth. Growth media and auxotrophic mutants strongly influenced respiratory metabolism. Most genes uncovered in the mutant screens have not been implicated in respiration in budding yeast. We applied gene-expression profiling approaches to compare steady-state fermentative and respiratory growth and to analyse the dynamic adaptation to respiratory growth. The transcript levels of most genes functioning in energy metabolism pathways are coherently tuned, reflecting anticipated differences in metabolic flows between fermenting and respiring cells. We show that acetyl-CoA synthase, rather than citrate lyase, is essential for acetyl-CoA synthesis in fission yeast. We also investigated the transcriptional response to mitochondrial damage by genetic or chemical perturbations, defining a retrograde response that involves the concerted regulation of distinct groups of nuclear genes that may avert harm from mitochondrial malfunction.

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An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis

Cited by 1,162 publications

References 59 publications

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Phototransduction Influences Metabolic Flux and Nucleotide Metabolism in Mouse Retina

Metabolic inhibitors accentuate the anti-tumoral effect of HDAC5 inhibition

Functional and Regulatory Profiling of Energy Metabolism in Fission Yeast

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