Cellular Metabolism, Adaptation and Toxicology

I. Cellular Metabolism, Adaptation and Toxicology
Metabolism is the foundation of all living organisms and plays a critical role in survival, proliferation and death. The metabolic profile provides a molecular snapshot of a cell at a given time and enables the exploration of the biochemical state of an organism. Using metabolomic and proteomic approaches we are studying various cellular functions/abnormalities.

1. Tricarboxylic acid cycle and cellular stress (metal, nutrient, ROS )
We have uncovered a pivotal role of a-ketoglutarate as a ROS scavenger. This keto acid is a very crucial component of the TCA cycle and its homeostasis in stressed cells (microbial, hepatocytes and astrocytes) is being elucidated. The metabolic network involving a-ketoglutarate dehydrogenase (KGDH), isocitrate dehydrogenase (ICDH) and glutamate dehydrogenase (GDH) is being delineated and the role of a-ketoglutarate as an antioxidant is being examined.

The TCA cycle

Furthermore, the contribution of the TCA cycle as an anti-oxidative and ATP-generating engine is also being studied.

2. NADPH homeostasis
Life is based on the interaction among NADH, NADPH and ATP. A high level of NADH and ATP (oxidative environment) leads to death while a high level of NADPH and ATP (reductive environment) promotes life. Hence, there is an intricate interaction among these three metabolites.

Metabolic circuits mediating the production of NADPH from NADH are being explored. NAD + kinase and NADH kinase, that play a prominent role in NAPDH production, are being studied as are the various enzymes like ICDH, glucose 6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), GDH-NADP (NADP + -dependent glutamate dehydrogenase) and 6-phosphogluconate dehydrogenase (6PGDH) that contribute to NADPH budget. We have recently uncovered a novel metabolic circuit involved in the conversion of NADH into NADPH.

3. Metal toxicology and energy production
Metal pollutants and cellular metal imbalance are a major cause of concern due to their negative impact on all living systems and on human health in particular. We are investigating how metals such as Al, Be, Zn and Pb affect metabolism and the production of ATP. We have discovered that the toxicity of Al is associated primarily with its ability to generate ROS and deprive the cells of Fe. As Al is a pro-oxidant and Fe-limiting it severely perturbs the TCA cycle and oxidative phosphorylation.

4. Metabolic diseases
Metabolic malfunctioning is the main cause of such diseases as obesity, hypertension, cancers, and atherosclerosis. Using liver (hepatocyte) and brain (astrocyte) cells as model systems, we are studying the metabolic changes triggered by abnormal levels of nutrients, metals and ROS . We have recently reported that the liver cells become lipogenic (fat producing) when challenged with Al. As ATP production is markedly diminished, nutrients (glucose, glutamine and fructose) fed to liver cells are converted into triglycerides. The ability of metal-stressed liver to utilize amino acids is also being investigated.

Furthermore, we are also finding that loss of cognitive power during ageing may be an adaptive response tailored to extend our life. As the brain is the main consumer of ATP (~85%), our body decides to “pull the plug” on this organ. This allows our system to limit the production of ROS , a by-product of ATP formation by modulating the TCA cycle and thus extends our longevity.