Uncovering the Effects of Hypoxia in CNS Disorders Using Whitley Workstations

November 5, 2019
By: Don Whitley Scientific Product News

CNSDisorders

Dr Scott Allen (pictured above) is a Lecturer in Neuroscience at the Sheffield Institute for Translational Neuroscience (SITraN). Part of the University of Sheffield, SITraN is one of the world leading centres for research into Motor Neurone Disease, Alzheimer’s and Parkinson’s Disease.
drAllen
We recently spoke to Dr Allen about his research, which focuses on how hypoxia (low oxygen) affects the metabolism of people with neurological disorders. Dr Allen remarked that historically it has been difficult to measure metabolism under hypoxic conditions due to the lack of available technology. Now, with the Whitley H35 HEPA Hypoxystation, it is possible to expose astrocytes (brain cells) to different levels of hypoxia and then asses how the metabolic profile of the cells has altered using a Seahorse Analyzer housed inside a Whitley i2 Instrument Workstation.

“Scientific advancement goes hand-in-hand with technological advancement; now we have this ability to measure and assess how hypoxia affects the metabolic profile of neurological diseases… we can hopefully improve the quality of life for people with Alzheimer’s and Motor Neurone Disease, and also extend their lives as well.”

To learn more about Dr Allen’s research, watch our video here.

Hypoxia researchers win the 2019 Nobel Prize in medicine

By: Katherine Ellen Foley
October 7, 2019
Click here to read the original article at www.msn.com

This year’s Nobel Prize in medicine was awarded to three scientists whose work focused on understanding how our cells take in various levels of oxygen.

This fundamental process is key to embryonic development, adapting to high altitude, and exercising. The Nobel Assembly based at the Karolinska Institute in Sweden, which made the announcement early on the morning of Oct. 7, also noted that the process plays a role in developing treatments for anemia, a common blood disorder in which there aren’t enough red blood cells able to carry oxygen to different tissues in the body, along with various type of cancers.

The winners of the prize—William Kaelin Jr., currently at Harvard Medical School and the Howard Hughes Medical Institute in Maryland; Sir Peter Ratcliffe, currently at the University of Oxford and Francis Crick Institute in London; and Gregg Semenza, currently at Johns Hopkins University in Maryland—will split the prize money, worth just over $9 million, equally. Want to understand why their work is important? Take a deep breath, and get ready to dive in.

Every one of your trillions of cells—and really, all animal cells everywhere on the planet—use oxygen from the air to turn food into usable energy.

Read more: Hypoxia researchers win the 2019 Nobel Prize in medicine

Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic elF5B

Author: J.J. David Ho et al.
Date: January 2018

Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic eIF5B

eIF5B is a GTPase eukaryotic translation initiation factor found on ribosomes which positions the initiation methionine tRNA on start codons of respective mRNA to ensure translation accurately initiates. It is speculated that aerobic eukarya retained eIF5B to remodel anaerobic pathways during episodes of oxygen deficiency.

The authors developed a method with the capability to generate an architectural blueprint of biologically active cellular translational machineries, termed MATRIX. This method combines metabolic pulse labeling, ribosome density fractionation and high-throughput mass spectrometry. MATRIX was employed to compare the protein abundance in polysome fractions (active translation) to that of free fractions (translationally disengaged) in both normoxic and hypoxic cells, ultimately proving that eIF5B concentrates in hypoxic translating ribosomes.

Read more: Oxygen-Sensitive Remodeling of Central Carbon Metabolism by Archaic elF5B

The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” Versus Oncogene Addiction

Author: Giulia Cheloni, et al
Date: June 2017

The Leukemic Stem Cell Niche: Adaptation to "Hypoxia" Versus Oncogene Addiction

Hematopoietic stem cells (HSC) are responsible for constantly maintaining and replenishing the supply of new blood and immune cells. They give rise to both lymphoid and myeloid progenitor cells, which then proceed to differentiate down their respective paths to form various specialized cells such as erythrocytes, macrophages, B and T cells, to name a few. Within the body, HSCs are found to reside in special locations termed “stem cell niches.” Stem cell niches (SCN) are sites in bone marrow dedicated to the long term maintenance of hematopoietic stem cells. HSC’s proliferate within SCN environments without losing stem cell potential i.e. they partake in self-renewal without differentiating – a defining characteristic of stem cells.

Unfortunately, like all other regulated cell cycles, the renewal and differentiation of HSC’s can succumb to replication errors which gives rise to many forms of cancer, namely those within the leukemia and lymphoma families. Leukemia diseases specifically, arise when myeloid progenitor cells become malignant aberrant cells naturally called leukemic stem cells (LSC). In this paper, Cheloni et al. primarily focused on chronic myeloid leukemia (CML). In CML, a translocation of DNA occurs between chromosomes 9 and 22, resulting in the production of the gene BCR-Abl which causes CML cells to expand and replicate.

Read more: The Leukemic Stem Cell Niche: Adaptation to “Hypoxia” Versus Oncogene Addiction

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.

Read more: Poldip2 is an oxygen-sensitive protein that controls PDH and αKGDH lipoylation and activation to...