- Last Updated: 10 January 2016 10 January 2016
The role of mitochondria in cellular function
Except for red blood cells 1, every cell of the human body contains mitochondria—which are cellular bodies that manufacture the energy needed by the cell in order to function. The energy is essentially created by the conversion of ATP (adenosine triphosphate) to ADP (adenosine diphosphate). Thus, a molecule of adenosine with three phosphate molecules attached becomes adenosine with two phosphate molecules attached, and energy is released during the reaction. In a reverse chain of chemical reactions, ATP can be created from ADP or from AMP, which is adenosine with one phosphate molecule attached. All of these reactions involve multiple chemicals and enzymes. The ATP is initially derived from either carbohydrate (in the form of glucose or glycogen (a form of glucose stored in cells)) or fatty acids. 2
Glycolysis is the metabolic pathway in mitochondria that converts glucose/glycogen into pyruvate and hydrogen. The pyruvate is transformed into acetyl-coenzyme A (acetyl –CoA). If there is sufficient oxygen, the acetyl-CoA then undergoes the Krebs cycle (also called the citric acid cycle). The biochemistry of the Krebs cycle is very complex. 2, 3, 4 We will not go into it here. The rate of the Krebs cycle transformations determines how much ATP is ultimately generated. 3 The Krebs cycle involves vitamin B-1 (thiamine), vitamin B-2 (riboflavin), magnesium, and malate (from malic acid), which has implications for treatment of mitochondrial disorders. 2
As a result of the Krebs cycle and what is called the Electron Transport Chain, ADP is transformed into ATP. (This transformation of ADP into ATP using oxygen is called oxidative phosphorylation.) Reactive oxygen species (ROS) build up as a byproduct and these damage mitochondrial membranes (inner and outer), cellular RNA, cellular DNA, proteins made by the cell, and cellular membranes .4, 5 Damage caused by ROS is called oxidative stress. ROS can cause apoptosis of the cell (cellular suicide.) 4, 5, 6, 7
If there is not sufficient oxygen, then less ATP is created and lactate builds up as a byproduct. To quote from Wikipedia 8 (which is an exposition of material in Science 9):
“When the energy in ATP is utilized during cell work (ATP hydrolysis), protons are produced. The mitochondria normally incorporate these protons back into ATP, thus preventing buildup of protons and maintaining neutral pH. If oxygen supply is inadequate (hypoxia), the mitochondria are unable to continue ATP synthesis at a rate sufficient to supply the cell with the required ATP. In this situation, glycolysis is increased to provide additional ATP, and the excess pyruvate produced is converted into lactate and released from the cell into the bloodstream, where it accumulates over time. While increased glycolysis helps compensate for less ATP from oxidative phosphorylation, it cannot bind the protons resulting from ATP hydrolysis. Therefore, proton concentration rises and causes acidosis.”
We will discuss the consequences of this below in the section on the characteristics and consequences of mitochondrial dysfunction fatigue.
When there is insufficient glucose/glycogen for the mitochondria to synthesize ATP, then fatty acids are used as a fuel source. This involves the release of fatty acid from fat cells into the blood stream, “activation” and transport of the free fatty acids into the mitochondria of a cell, and the break-down of the fatty acid into acetyl-CoA, which ultimately yields ATP. This last step is called beta-oxidation. 2, 10 Unfortunately, the process of the activation and transport of long chain fatty acid into mitochondria involves breaking down ATP into byproducts and transporting the relevant byproduct (acyl-CoA—which isn’t the same as acetyl-CoA) via what is called the carnitine transport system. 2, 10, 11, 21 Thus ATP has to be used to transport a byproduct of fatty acid into the mitochondria in order to create more ATP.
Once in the mitochondria, the acyl-CoA is transformed into acetyl-CoA as part of beta-oxidation. After acetyl-CoA is created, it enters the Krebs cycle and the process of creating ATP is like that for creating ATP from glucose using oxygen. Involved in the transport system and beta-oxidation are acetyl-carnitine, co-enzyme Q-10, biotin, and vitamin B-12, which has implications for the treatment of mitochondrial disorders. 2, 10, 11, 12
Most types of cells can utilize fatty acid as a fuel except for the cells of the brain. 10 When the cells of the liver utilize fatty acid in their mitochondria, they generate chemicals called ketone bodies. The ketones then enter the blood stream. All cells of the body, including brain cells, can use ketones as an alternate source of energy. 10
Generally speaking, cells prefer to use glucose as a fuel, under oxygenation. During fasting, fatty acids and ketone bodies are more important energy sources for most cells, with the idea that the glucose available is saved for brain cells. 10 The situation in skeletal muscle cells is more complicated. The choice of fuel source is largely determined by exercise intensity and duration. As exercise intensity increases, the use of glucose/glycogen intensifies. However, at low intensity or moderate exercise, fatty acid is the preferred fuel .10, 11 As for the heart, fatty acids are the preferred fuel for 60-90% of its energy needs. 14