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

Author: Felipe Paredes et al.
Date: January 2018
Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to support metabolic adaptation in hypoxia and cancer

In this paper, the authors show that poldip2 governs the critical mechanism linking clp, ACSM1, and protein lipoylation; thus, regulating mitochondria function.

Lipoylation of two key enzymes in the TCA cycle, PDH and αKGDH, is a dynamically regulated process that is inhibited under hypoxia and in cancer cells, resulting in restricted mitochondria function. Poldip2, a ubiquitously expressed protein, regulates the lipoylation of both pyruvate and αKDH subunits via regulation of the clp-protease complex (CLPX ) and deregulation of the lipoate-activating enzyme required for lipoylation in mammalian cells, Ac-CoA synthetase (ACSM1). In Poldip2-defficient cells, repressed mitochondria function induces the stabilization of HIF-1α, thereby reprogramming cellular metabolism to resemble hypoxic/cancer cell adaption. Additionally, Poldip2 is down-regulated in hypoxic environments, further stabilizing HIF-1α while also inducing the expression of PDH kinase (PDK), consequently inhibiting lipoylation.

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Dr. Rey of the Princess Margaret Cancer Centre in Toronto, Canada, and his co-authors Luana Schito, Marianne Koritzinsky and Brad Wouters have contributed vastly to our knowledge about the cellular response to hypoxia in the context of tumor behavior. Since 2009, they have acquired 4 HypOxystations for their lab, in order to culture cells under conditions which authentically mimic the physiological environment of cancer. The HypOxystation provides a closed workstation format for rigorous control of oxygen, CO2, temperature and humidity, facilitating accurate regulation of cell culture conditions as the in vivo tumor situation is simulated. An extensive list of publications from our HypOxystation users spans the whole breadth of research into metabolic, epigenetic and therapeutic implications of hypoxia.

Read more: Molecular Targeting of Hypoxia in Radiotherapy

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From: Satani et al. (2016) “ENOblock Does Not Inhibit the Activity of the Glycolytic Enzyme Enolase” PLoS ONE 11(12):e0168739. doi:10.1371

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Read more: Adaptation to Stressors by Systemic Amyloidogenesis