Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis, 2022, Allen et al

[SNT Gatchaman]

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis
Allen CNS, Arjona SP, Santerre M, Sawaya BE

Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways.

Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

Link | PDF (Viruses)

 

[SNT Gatchaman]

Good review paper, which gives background to current investigations into EBV and other viral latency/reactivation, itaconate shunt among others. Will probably require a few read-throughs and a bit of note-taking I'm finding...

 

[SNT Gatchaman]

Hard to select a few quotes without reproducing the whole paper (which is open-access, so I've been liberal). Some reformatting for legibility —

Metabolic reprogramming is a crucial area of study in cancer and is listed as a hallmark of cancer. Dr. Otto Warburg first described metabolic reprogramming while studying the properties of tumorigenic cells. He observed an increase in the metabolism of glucose, known as glycolysis, and a subsequent high concentration of lactic acid. Dr. Warburg noted that this increase in glycolysis was taking place even in the presence of oxygen. Typically, the cell utilizes mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is the only* available resort to upregulating glycolysis in a hypoxic environment. For that reason, the finding that cancer cells act as hypoxic cells was surprising.

*That penultimate sentence is a little confusing and I wonder if it should read more as: "Typically, the cell utilizes mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available, and only resort to upregulating glycolysis in a hypoxic environment."

In addition to cancer cells, viruses also depend on biomass to fuel viral replication and production of new virions; therefore, they depend on metabolic reprogramming.

Metabolic reprogramming is an integral part of both cancer and viral infections, not only to provide the materials for the large-scale biosynthesis for rapid replication and survival but also to provide energy for these processes. We classified changes in cellular metabolism that contribute to metabolic reprogramming in six [seven?] main hallmarks:

(1) increased glycolysis and lactic acid
(2) increased pentose phosphate pathway (PPP)
(3) increased glutaminolysis
(4) mitochondrial changes
(5) increased lipid metabolism
(6) changes in amino acid metabolism
(7) changes in other biosynthetic and bioenergetic pathways.

In normal cells, glucose is converted into pyruvate through regulated enzymatic reactions called glycolysis. Pyruvate is then transformed into acetyl coenzyme A (acetyl-CoA), which fuels the tricarboxylic acid cycle (TCA cycle) [...] products are used in the mitochondrial respiratory chain through oxidative phosphorylation (OXPHOS) to produce 36 molecules of cellular energy in the form of adenosine triphosphate (ATP).

Because glycolysis produces only two molecules of ATP, cells must compensate for the reduction of ATP by upregulating the amount of glucose that undergoes glycolysis

Hence, cells first need to increase the uptake of glucose. Many cells achieve this by activating glucose transporters. Additionally, metabolic reprogrammed cells exhibit an increase in glycolytic enzymes to promote further glycolysis. Cells experiencing metabolic reprogramming utilize HIF-1α and c-Myc transcription factors, master inducers of glycolysis, to upregulate glucose transporters and glycolytic enzymes

Mitochondria are essential components for many metabolic pathways, namely the TCA cycle and the electron chain. They are crucial for maintaining many aspects of cellular homeostasis. During metabolic reprogramming, mitochondria change from primarily being used for energy production, by way of the mitochondrial electron transport chain, to playing a role in generating TCA cycle metabolites to be used in the biogenesis and redox balance

The increase in lipid metabolism is another hallmark because lipids are essential building blocks for cancer and viruses to create new organelles, cells, and virions

Although most metabolic research was performed in the cancer field, viruses also take advantage of these pathways to produce the material and environment needed to sustain a large output of virions. The results of metabolic reprogramming in viral infections provide the virus with free nucleotides for viral genome replication, amino acids for virion assembly, and lipids for membrane formation to envelope the virion

Metabolic reprogramming has many non-metabolic effects on the cell. These can include increased inflammation, anti-apoptosis, immune evasion, and the production and accumulation of advanced glycation end products (AGEs)

The hallmarks of metabolic reprogramming represent the cellular processes deregulated in diseases that affect cellular metabolism. These diseases include cancers and viruses that hijack a cell’s energy source and rewire it to produce biomass needed for proliferation and virion production.

Many of the hallmarks of metabolic reprogramming outlined here represent ways in which a cell may feed metabolites back into the TCA cycle. As glycolysis is continuing to be promoted and yet the conversion of pyruvate to acetyl-CoA is not occurring, the use of the TCA cycle for energy slows down.

However, the TCA cycle is critical for producing metabolites used in the production of biomass. Therefore, viruses may target any number of enzymes or shuttles at any step along the way to ensure the cell is only working to produce more virions. Over time, as viruses continued to benefit from the non-metabolic effects of metabolic reprogramming, they evolved to generate an environment conducive to the replication of virions and immune evasion.