ATP Synthase: the Understood, the Uncertain, and the Unknown Part 1 of 5

Introduction

Thank you very much. I’ve never received such a greeting before. I’ve seen Ron introduce people, and now I will talk about ATP synthase, an enzyme I’ve studied for more than 30 years.

Basic Facts about ATP Synthase and Mitochondria

What you see is a representation of the inner membrane of the mitochondrion. Sugars are broken down to pyruvate by glycolysis, and pyruvate is transported into mitochondria by a mechanism we still don’t fully understand. There it encounters pyruvate dehydrogenase, producing acetyl-CoA and generating reducing equivalents.

The acetyl-CoA feeds into the Krebs cycle, and out of that come more reducing equivalents. Fats in food are transported into mitochondria as acyl groups attached to coenzyme A. These acyl groups are transferred to carnitine and then transported into the mitochondrion, where they reattach to coenzyme A inside the mitochondrion and enter the beta-oxidation pathway, producing more reducing equivalents.

Ultimately, energy in fats and sugars is turned into redox energy, which feeds into the electron transport chain, generating the proton motive force across the inner mitochondrial membrane. The ATP synthase enzyme utilizes this proton motive force to generate adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate.

Electron Transport Chain and Proton Motive Force

Here’s a simplified version depicting the main players in the respiratory chain in mitochondria. Reducing equivalents feed into the electron transport chain via Complex I, a large structure with many proteins. In mammalian mitochondria, Complex I contains 45 proteins with a mass of about a megadalton. The bacterial counterpart is simpler and has been solved first.

Complex I transfers protons across the membrane using redox energy. The protons are transferred onto coenzyme Q in the membrane. Complex II, or succinate dehydrogenase, feeds more reducing equivalents into the chain, but it does not translocate protons. Reduced Q then goes to Complex III, cytochrome bc1, converting more redox energy into proton motive force. Cytochrome c then transfers electrons to Complex IV, cytochrome c oxidase, where oxygen is reduced to water. This is where most of the oxygen we breathe is utilized.

ATP Synthase Function

The proton motive force generated feeds into the ATP synthase enzyme, driving the conversion of ADP and phosphate into ATP. The generated ATP is transported into the cell by ADP/ATP translocase, exchanging it with external ADP. Another transporter, the phosphate carrier, brings back phosphate into the mitochondrion. Thus, there’s a cycle of ATP being generated and used as fuel. We produce about 50 to 60 kilograms of ATP daily.

Complex I and ATP Synthase Structure

Complex I’s structure, solved by Leonid Sazanov, shows a significant accomplishment. The electron transfer site is hosted 100 angstroms from the membrane domain, connected through a wire of iron-sulfur clusters. While the mechanism is not completely understood, clues about the role of sodium-proton antiporters and the orthogonal helices suggest a piston-like action might be at play.

In the 1980s, we knew the ultrastructure of ATP synthase, its binding change mechanism by Paul Boyer, and the subunit composition. However, many aspects, like exact subunit numbers and sequences, were unknown due to the technological limits of the time.

In conclusion, while significant advancements have been made in understanding ATP synthase, much remains to be discovered.

Keywords

• ATP Synthase
• Electron Transport Chain
• Proton Motive Force
• Mitochondria
• Redox Energy
• Complex I
• Complex II
• Cytochrome bc1
• Cytochrome c Oxidase
• ADP/ATP Translocase
• Phosphate Carrier
• Acetyl-CoA
• Beta-Oxidation
• Glycolysis
• Krebs Cycle

FAQ

Q1: What is ATP Synthase?

A1: ATP synthase is an enzyme in the inner membrane of mitochondria that synthesizes ATP from ADP and phosphate using the proton motive force generated by the electron transport chain.

Q2: How is proton motive force generated?

A2: Proton motive force is generated by the electron transport chain as electrons move through complexes I, III, and IV, transferring protons across the inner mitochondrial membrane.

Q3: What is the role of the electron transport chain?

A3: The electron transport chain creates a proton gradient across the inner mitochondrial membrane, which ATP synthase then uses to produce ATP.

Q4: How are fats converted to energy in mitochondria?

A4: Fats are transported into mitochondria as acyl groups attached to coenzyme A. They enter the beta-oxidation pathway, producing reducing equivalents that feed into the electron transport chain.

Q5: How much ATP does a human produce daily?

A5: An average human produces about 50 to 60 kilograms of ATP daily, an amount roughly equivalent to their body weight.