Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

Paredes, Felipe; Sheldon, Kely L.; Lassègue, Bernard; Williams, Holly C.; Faidley, Elizabeth A.; Benavides, Gloria A.; Torres, Gloria; Sanhueza–Olivares, Fernanda; Yeligar, Samantha M.; Griendling, Kathy K.; Darley‐Usmar, Victor; Martin, Alejandra San

doi:10.1073/pnas.1720693115

Cited by 58 publications

(54 citation statements)

References 36 publications

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“…Mechanisms involved in regulation of PDC activity by tumor hypoxia. Hypoxia decreases PDC activity (more details in text) by: HIF‐1‐mediated transcription of PDHK1 and PDHK3, which inhibit PDC by phosphorylation of E1α ( 1 ); HIF‐1‐induced transcription of LONP protease that degrades E1β ( 2 ); downregulation of Poldip2, resulting in increased degradation of the lipoic‐acid activating enzyme ACSM1, which leads to decreased E2 lipoylation and PDC activity, accompanied by decreased α‐ketoglutarate (αKG) levels that additionally inhibit prolyl‐hydroxylases (PHDs) and stabilize HIF‐1α ( 3 ); activating PDHK1 by post‐translational phosphorylation of its threonine residues either by ERK‐phosphorylated and mitochondrially‐translocated phosphoglycerate kinase 1 (PGK1) ( 4 ) or by mitochondrially‐translocated phosphorylated Akt ( 5 ); prolyl‐hydroxylase PHD3 depletion that leads to PDC destabilization due to decreased PHD3‐E1β interaction ( 6 ) …”

Section: Resultsmentioning

confidence: 99%

“…( b ) Post‐translational regulation of PDC activity (details in text). (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13) …”

Section: Mechanistic Regulation Of Pdcmentioning

confidence: 99%

Section: Emerging Mechanisms Of Post‐translational Control Of Pdc Actmentioning

confidence: 99%

“…Furthermore, hypoxia reduces E2 lipoylation and PDC activity via Poldip2 (polymerase‐δ interacting protein 2) downregulation . Poldip2 indirectly protects the lipoic‐acid activating enzyme ACSM1 from degradation resulting in lipoylated E2 and active PDC . Additionally, Poldip2 loss led to decreases in α‐ketoglutarate levels and subsequent normoxic stabilization of HIF‐1α, PDHK induction and PDC E1α phosphorylation, further contributing to low mitochondrial function …”

Section: Emerging Mechanisms Of Post‐translational Control Of Pdc Actmentioning

confidence: 99%

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Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Golias

Kery

Radenkovic

et al. 2018

Intl Journal of Cancer

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During malignant progression cancer cells undergo a series of changes, which promote their survival, invasiveness and metastatic process. One of them is a change in glucose metabolism. Unlike normal cells, which mostly rely on the tricarboxylic acid cycle (TCA), many cancer types rely on glycolysis. Pyruvate dehydrogenase complex (PDC) is the gatekeeper enzyme between these two pathways and is responsible for converting pyruvate to acetyl-CoA, which can then be processed further in the TCA cycle. Its activity is regulated by PDP (pyruvate dehydrogenase phosphatases) and PDHK (pyruvate dehydrogenase kinases). Pyruvate dehydrogenase kinase exists in 4 tissue specific isoforms (PDHK1-4), the activities of which are regulated by different factors, including hormones, hypoxia and nutrients. PDHK1 and PDHK3 are active in the hypoxic tumor microenvironment and inhibit PDC, resulting in a decrease of mitochondrial function and activation of the glycolytic pathway. High PDHK1/3 expression is associated with worse prognosis in patients, which makes them a promising target for cancer therapy. However, a better understanding of PDC's enzymatic regulation in vivo and of the mechanisms of PDHK-mediated malignant progression is necessary for the design of better PDHK inhibitors and the selection of patients most likely to benefit from such inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…( b ) Post‐translational regulation of PDC activity (details in text). (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13) …”

Section: Mechanistic Regulation Of Pdcmentioning

confidence: 99%

Section: Emerging Mechanisms Of Post‐translational Control Of Pdc Actmentioning

confidence: 99%

Section: Emerging Mechanisms Of Post‐translational Control Of Pdc Actmentioning

confidence: 99%

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Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Golias

Kery

Radenkovic

et al. 2018

Intl Journal of Cancer

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“…We appreciate Bailey et al's (1) interest in our publication (2), in which we define a role for polymerase-δ interacting protein 2 (Poldip2) in controlling a salvage pathway of lipoylation. Our study builds on a substantial body of evidence, indicating that the mammalian mitochondrial lipoyltransferase LIPT1 lipoylates using lipoyl-AMP.…”

mentioning

confidence: 99%

Reply to Bailey et al.: New perspectives on the novel role of the Poldip2/ACSM1 axis in a functional mammalian lipoylation salvage pathway

Paredes¹,

Lassègue²,

Williams³

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Transmembrane Potential Monitoring Using a Field‐Effect Transistor‐Based Flexible Device System

Xue,

Zhou,

Guo

et al. 2024

Adv Materials Inter

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Transmembrane transport analysis is essential for understanding cell physiological processes. Based on an artificial simulation of internal and external cellular environment, this paper introduces an innovative approach to investigate the microscopic behavior of small molecules through porin protein under mechanical curvature of lipid membrane. A flexible device system is developed, enabling quantitative electronic transmembrane analysis. The key transistor comprises a flexible, microporous electrode covered with the support lipid bilayers (SLBs) to mimic artificial cellular membrane, serving as an extended gate of the field‐effect transistor (FET). The transmembrane behaviors of charged ions and small molecules can be effectively monitored in real time by this FET‐based flexible device system. The flexibility of the electrode allows analyzing the transmembrane behavior under different mechanical bends. In this study, the developed flexible device is employed for the first time to simulate the mechanical bending of cellular membrane embedded with channel proteins and to monitor the transmembrane behavior of small molecules, thus providing a more authentic representation of membrane protein at a curved state. This approach holds the potential to contribute as a platform‐based technological advancement, supporting research into toxicological mechanisms and facilitating drug screening endeavors.

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Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

Cited by 58 publications

References 36 publications

Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Microenvironmental control of glucose metabolism in tumors by regulation of pyruvate dehydrogenase

Reply to Bailey et al.: New perspectives on the novel role of the Poldip2/ACSM1 axis in a functional mammalian lipoylation salvage pathway

Transmembrane Potential Monitoring Using a Field‐Effect Transistor‐Based Flexible Device System

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