Metabolics and Mitochondria and Inflammation
Mitochondria and Inflammation
Mitochondria are tiny organelles inside cells that generate energy from food in the form of ATP (adenosine triphosphate). This process is known as cellular respiration. It is for this reason that mitochondria are often referred to as powerhouses of the cell. Mitochondrial function is particularly impacted by sirtuins (SIRTs), uncoupling proteins (UCPs), antioxidant and inflammatory genes.
As seen in the Nutrient Sensing section, SIRTs are an NAD+ (nicotinamide adenine dinucleotide) dependent family of signalling proteins involved in metabolic regulation. Sirtuin 3 (SIRT3) is expressed in the mitochondria and hence plays an important role in regulating energy metabolism – fatty acid oxidation, the Krebs cycle, the ETC (electron transport chain) and ROS (reactive oxygen species) detoxification.
The Krebs cycle is the main source of energy for cells. It takes in Acetyl-CoA (from glucose and fats) and with the help of cofactors NAD+, FAD (flavin adenine nucleotide), generates NADH, FADH2 and ATP. Subsequently, the protons (H+ ions) and electrons released from NADH and FADH2, are processed by the ETC with cofactors CoQ10, iron and copper. The protons couple with ATP synthase to produce ATP.
Uncoupling Proteins
Uncoupling proteins return the free, uncoupled, protons from the (mitochondria) intermembrane space to the matrix and release energy in the form of heat. By removing protons, the UCPs help prevent ROS production and mitochondrial damage.
Brown adipose tissue (BAT) is activated in cold conditions and has a high concentration of UCPs, enabling greater metabolic activity. It is more present in women than in men, decreases with age, and can be induced by PGC1A, cold exposure, leptin, exercise, adrenaline, green tea, cabbage, berries, spinach and capsaicin. UCP1, known as thermogenin, is exclusively found in BAT.
A SNP on UCP1 is associated with reduced expression, impaired energy metabolism and lower resting metabolic rate. This can promote fat storage, increased BMI and obesity (especially lower body). It is also associated with high triglycerides, high LDL and low HDL. Purine nucleotides (found in high fructose corn syrup, seafood, organ meat and alcohol) inhibit UCP1, whereas fatty acids activate it.
UCP2 and UCP3 specifically regulate fatty acid oxidation and reduce the formation of ROS. A SNP on UCP2 is associated with lower activity and risk of higher BMI, obesity and type 2 diabetes. UCP3 protects from lipid-induced oxidative stress by removing excess fatty acids. A polymorphism on UCP3 is associated with decreased expression, inflammation, higher risk of obesity, insulin resistance, higher LDL cholesterol, non-alcoholic fatty liver disease, type 2 diabetes and other symptoms of metabolic dysfunction, particularly in Asian populations. Physical activity has been shown to increase UCP3 activity. A high-fat diet is not recommended for SNP carriers.
Antioxidant Cascade
During cellular respiration, ROS (free radicals) are formed within the mitochondria. These by- products include superoxide anion, hydrogen peroxide (H2O2), and hydroxyl radical, which are highly reactive. While ROS are essential signalling molecules, excess can lead to oxidative stress, which can damage cells, proteins, lipids and DNA, and contribute to biological ageing. Oxidative stress also leads to symptoms of metabolic syndrome – obesity, diabetes, cancer, neurodegenerative and cardiovascular diseases.
Antioxidant defence is the ROS scavenging mechanism activated by SIRT3. By binding to FOXO3 (forkhead box family member 3), this sirtuin stimulates catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) which all have an antioxidant action. A SNP on SIRT3 is associated with increased activity, and improved metabolic function, healthier ageing and longer lifespan. SIRT3 is upregulated by caloric restriction, fasting, exercise, and its cofactor NAD+. However, SIRT3 activity reduces with age and a high-fat diet. Related to its antioxidant function, FOXO3 has been identified as a strong contributor to exceptional longevity. Curcumin and green tea help to induce FOXO3.
Working alongside FOXO3 to activate the antioxidant cascade is NRF2 (nuclear factor erythroid 2-related factor 2), often called the master antioxidant regulator. It also stimulates mitochondrial biogenesis. A SNP on NRF2 is associated with lower activity and reduced antioxidative capacity – due to knock-on effects on SOD2, CAT and GPX1. Aerobic exercise, caloric restriction/fasting, DHA (docosahexaenoic acid) – a type of omega-3 fat, and resveratrol have been shown to increase NRF2 activity.
The first step of the antioxidant defence mechanism is led by SOD2, which transforms superoxide into hydrogen peroxide and oxygen. A SNP on this gene can reduce SOD2 activity, leading to more oxidative stress and increased risk of free radical damage. Manganese is the main cofactor for SOD2.
In the second step, CAT and GPX1 convert hydrogen peroxide into oxygen and water. Polymorphisms on these genes reduce their antioxidant activity too and increase ROS levels. Their cofactors are manganese (for CAT), selenium and glutathione (for GPX1). Other small antioxidants that aid in mitochondrial protection are lipoic acid, vitamin E, CoQ10 and carnitine.
Inflammation
Mitochondrial ROS can lead to chronic inflammation. In return, pro-inflammatory compounds can also increase ROS levels, triggering a 'vicious cycle'. Increased activity of IL6 (interleukin 6), CRP (C-reactive protein), IFNG (interferon-gamma) and TNF (tumour necrosis factor), due to SNPs and environmental factors, can contribute to oxidative stress and stimulate metabolic, inflammatory and autoimmune diseases. Anti-inflammatory nutrients include omega-3 fatty acids, curcumin and green tea.