Complex III: Function and Role in Cellular Respiration

Complex III, also known as the cytochrome bc1 complex or ubiquinone-cytochrome c reductase, is an enzyme involved in cellular energy production. It functions within the mitochondria as part of a multi-step process that generates most of a cell’s usable energy. The enzyme acts as a middleman in this process, accepting electrons from one molecule and passing them to another.

Composition and Cellular Location

Complex III is embedded within the inner mitochondrial membrane, a selective barrier separating the mitochondrial matrix from the intermembrane space. It exists as a dimer, meaning two identical functional units are paired together. While each unit is built from multiple protein subunits, three are directly involved in its catalytic function: Cytochrome b, Cytochrome c1, and the Rieske iron-sulfur protein. Cytochrome b is encoded by mitochondrial DNA, while the other subunits are encoded by nuclear DNA. Both cytochrome subunits contain a heme group with an iron atom that can accept and donate a single electron, while the Rieske protein contains a different type of electron-accepting center, a 2Fe-2S iron-sulfur cluster.

Function in the Electron Transport Chain

The primary job of Complex III is to serve as a link in the electron transport chain. It accepts electrons from a mobile molecule called ubiquinol, which collects electrons from the first two complexes of the chain. After receiving a pair of electrons, Complex III transfers them one at a time to a small, water-soluble protein called cytochrome c. This electron transfer releases energy, which Complex III harnesses to pump protons (H+ ions) across the inner mitochondrial membrane. For every two electrons it passes to cytochrome c, it moves four protons from the matrix into the intermembrane space.

The Q Cycle Mechanism

The process by which Complex III handles electrons and pumps protons is the Q cycle. This mechanism solves a problem: the donor, ubiquinol, carries two electrons, but the acceptor, cytochrome c, can only carry one. The cycle maximizes the number of protons pumped and relies on two binding sites within the complex, the Qo (oxidation) site and the Qi (reduction) site.

The Q cycle occurs in two rounds. In the first round, a ubiquinol molecule binds to the Qo site and releases its two electrons. One electron is transferred to the Rieske iron-sulfur protein, then to cytochrome c1, and finally to cytochrome c. The second electron is sent through cytochrome b to a ubiquinone molecule at the Qi site, partially reducing it to a semiquinone radical. During this round, the two protons from the ubiquinol are released into the intermembrane space.

A second ubiquinol molecule then binds to the Qo site and initiates the second round. It repeats the process, sending one electron to reduce a second cytochrome c molecule. Its other electron is sent through cytochrome b to the Qi site. This second electron fully reduces the semiquinone radical, which picks up two protons from the matrix to become a new ubiquinol molecule.

The net result is the oxidation of two ubiquinol molecules, the reduction of two cytochrome c molecules, and the regeneration of one ubiquinol molecule. This process results in the movement of four protons into the intermembrane space. This recycling of one electron significantly increases the efficiency of energy conversion.

Contribution to the Proton-Motive Force

The continuous pumping of protons by complexes like Complex III creates a significant difference in proton concentration and electrical charge across the inner mitochondrial membrane. The intermembrane space becomes more acidic and positively charged relative to the matrix. This combined electrochemical gradient is called the proton-motive force. It represents a stored form of potential energy, much like water stored behind a dam.

This stored energy is the direct power source for the final stage of cellular respiration. Protons flow down their gradient from the intermembrane space into the matrix through a channel in an enzyme called ATP synthase. The flow of protons drives its molecular machinery, which synthesizes the vast majority of adenosine triphosphate (ATP), the cell’s main energy currency.

Consequences of Dysfunction

When Complex III does not function correctly, the consequences for the cell can be severe. Genetic mutations in the genes that code for its subunits can lead to a range of mitochondrial diseases. These disorders affect multiple organ systems, particularly those with high energy demands like the brain, heart, and muscles. Symptoms vary widely, from exercise intolerance to severe encephalopathy and liver failure.

A faulty Complex III can also disrupt the smooth flow of electrons. When the chain is blocked, electrons can leak out and react with oxygen molecules, forming highly reactive superoxide radicals. These radicals are a type of reactive oxygen species (ROS) that cause widespread damage to proteins, lipids, and DNA, a condition known as oxidative stress.