9.1 Challenges Associated with Oxygen Limitation

To produce large amounts of ATP, most eukaryotic cells require oxygen. By using aerobic respiration (which requires oxygen), cells can produce 30-38 ATP molecules from the energy stored in a single glucose molecule (Chapter 6). Starting with glycolysis and ending with oxidative phosphorylation, this metabolic pathway efficiently supplies ATP that is required to power many cellular processes. When a cell has limited or no access to oxygen, normal cell functioning is impaired. In this section, you will learn about how a cell functions under optimal oxygen levels and what happens when oxygen supply does not support the demands of the cell.

Understanding Hypoxia

Hypoxia occurs when a cell’s oxygen demand exceeds its oxygen supply. A cell may experience hypoxia due to increased demand for oxygen (e.g., increased metabolic activity) or a decreased supply of oxygen available (e.g., at high altitudes, Figure 9.2). Under extreme conditions, cells can experience the total absence of oxygen, or anoxia. It is important to note that not all cells experience hypoxia at the same level of oxygen. Some organisms (and therefore their cells) have adapted their physiology to survive at lower oxygen levels. For instance, the naked mole rat, who primarily reside underground are generally unbothered by the low oxygen content. However, other organisms, such as humans are not accustomed to such oxygen levels, and therefore do not inhabit those environments.

Cells are likely to experience hypoxia in terrestrial environments such as high-altitude areas or in aquatic environments with high abundance of algal species. High altitude hypoxia is caused by a decrease in the partial pressure of oxygen, making it more difficult for oxygen to diffuse into cells or be transported by hemoglobin. In aquatic environments, the overgrowth of algal blooms consumes available oxygen, leaving other cells and organisms in hypoxic stress. Cells that regularly experience hypoxia from their environment have certain strategies or have adapted in a way to withstand the effects (more in Chapter 9.3).

Human Health Example – Anemia

Anemia is a condition where one’s hemoglobin levels or red blood cell count is below average. Red blood cells are responsible for transporting oxygen to tissues of the body and hemoglobin is the protein which oxygen molecules bind to. With decreased hemoglobin or red blood cell levels, an anemic person’s cells would experience hypoxia as their cells are not receiving enough oxygen to meet cellular demands. A person with anemia may require iron supplements to boost hemoglobin levels and increase oxygen uptake.

Metabolism Under Normoxia

Normoxia (normal oxygen levels) is important for proper physiological functioning of cells that use aerobic cellular respiration, i.e., eukaryotic cells and many prokaryotic cells. When a cell has sufficient oxygen supply, it able to carry out aerobic pathways for ATP synthesis (Figure 9.3). In eukaryotic cells, aerobic respiration begins with glycolysis of glucose in the cytosol, resulting in production of 2 ATP and 2 pyruvate per glucose. In the mitochondrial matrix, pyruvate is oxidized to acetyl CoA, which is then consumed in the citric acid cycle (also called the TCA cycle or Krebs cycle) to produce 2 more ATP per glucose. However, most ATP from glucose oxidation (~26 ATP per glucose) is produced due to activity of the mitochondrial electron transport system (ETS) and ATP synthase embedded in the mitochondrial inner membrane. Oxygen is the terminal electron acceptor for ETS, and required for this large amount of ATP synthesis. When oxygen supply meets oxygen demands, lots of ATP can be produced from glucose and other organic molecules, and this ATP then supports lots of cellular activity, such as protein synthesis, active transport, growth, and reproduction.

Metabolism Under Hypoxia

Aerobic respiration is unable to function optimally or may cease entirely as oxygen availability becomes limited. The mitochondrial ETS cannot function without oxygen as the final electron acceptor, because without a final electron acceptor, no electrons can move through the ETS. Therefore, the cell cannot rely on aerobic respiration to produce lots of ATP. In order to maintain vital cellular processes, anaerobic respiration must occur instead (Figure 9.3). Anaerobic respiration processes, like fermentation, produce small amounts ATP in the absence of oxygen. In most animal cells, glycolysis can proceed as normal in the absence of oxygen, but pyruvate is reduced to lactate (rather than oxidized to acetyl CoA) through lactic acid fermentation. Other organisms such as yeast (and some animals like goldfish) use ethanol fermentation, converting pyruvate to ethanol and carbon dioxide. Through anaerobic respiration, the cell produces 2 ATP per glucose via glycolysis. This decreased production of ATP can fuel essential cellular functions (e.g., cell maintenance) while oxygen supply is limited. For most cells, anaerobic pathways are not sustainable long term due to the build up of toxic products (lactic acid, ethanol) from fermentation. High levels of lactic acid in cells can lead to lactic acidosis, which impacts metabolic functioning and damages the cell. Prolonged anaerobic respiration may lead to insufficient ATP generation, a failure to meet energy requirements, and ultimately cell death.

You may be asking the question: if ATP is produced in glycolysis, what is the point of carrying out processes like lactic acid or ethanol fermentation, which generate toxic molecules? If order for glycolysis to function, the cell needs a steady supply of the electron carrier NAD⁺. NAD⁺ gets reduced to NADH during glycolysis. Under aerobic conditions, NADH is reoxidized to NAD⁺ at the mitochondrial ETS (Figure 9.3). However, the ETS cannot facilitate this process during hypoxia or anoxia, so the cell needs another way to reoxidize NADH to NAD⁺. This is the purpose of fermentation: to reoxidize NADH to NAD⁺, so that glycolysis can continue producing small mounts of ATP.