What is the Krebs (Citric Acid) cycle?

The Krebs Cycle (Citric Acid Cycle): A Simple Explanation

The Krebs cycle is a circular metabolic pathway occurring in mitochondria that oxidizes acetyl-CoA (derived from carbohydrates, fats, and proteins) through a series of enzymatic reactions to generate energy in the form of ATP, along with electron carriers (NADH and FADH2) that fuel additional ATP production through oxidative phosphorylation. 1, 2

Core Function and Location

• The Krebs cycle, also called the tricarboxylic acid (TCA) cycle or citric acid cycle, takes place in the mitochondrial matrix of eukaryotic cells 1, 2
• It serves as the "final common pathway" for oxidizing nutrients from carbohydrates, fatty acids, and amino acids into usable cellular energy 1, 3
• This pathway is central to aerobic metabolism and represents a critical hub where catabolic (breakdown) and anabolic (building) processes intersect 2, 3

How the Cycle Works: Step-by-Step

The cycle begins when acetyl-CoA (a 2-carbon molecule) combines with oxaloacetate (a 4-carbon molecule) to form citrate (a 6-carbon molecule) 1, 4. This is the entry point into the cycle.

Through a series of enzymatic reactions, citrate is progressively broken down:

• Two carbon dioxide (CO2) molecules are released as waste products during the cycle 1
• Energy carriers are generated: three NADH molecules, one FADH2 molecule, and one ATP (or GTP) molecule per cycle turn 1
• Oxaloacetate is regenerated at the end, allowing the cycle to continue 4, 2

The NADH and FADH2 produced then donate electrons to the electron transport chain in the inner mitochondrial membrane, where they drive the production of additional ATP through oxidative phosphorylation 1, 3.

Key Regulatory Points

• Oxaloacetate availability is the critical branch point that determines whether acetyl-CoA enters the TCA cycle or is diverted to alternative pathways like ketogenesis 4
• When oxaloacetate is depleted (such as during fasting or when diverted to gluconeogenesis), acetyl-CoA accumulates and cannot enter the cycle efficiently 1, 4
• The cycle is highly regulated by substrate availability, energy status of the cell, and hormonal signals 2, 5

Beyond Energy Production

The Krebs cycle is not just about energy—it's an "amphoteric pathway" that serves dual purposes 3:

• Catabolic function: Breaking down nutrients to generate ATP and reducing equivalents 2
• Anabolic function: Providing intermediates (building blocks) for biosynthesis of amino acids, nucleotides, lipids, and glucose 1, 3

For example, intermediates from the cycle supply carbon skeletons for non-essential amino acid synthesis and contribute to gluconeogenesis (glucose production from non-carbohydrate sources) 1, 6.

Clinical Relevance

Disruption of the Krebs cycle leads to serious metabolic dysfunction 1:

• In insulin deficiency (Type 1 diabetes), decreased oxaloacetate synthesis from pyruvate impairs the cycle, leading to deficient ATP production and ketosis development 1
• Mitochondrial disorders affecting respiratory chain function directly compromise Krebs cycle efficiency, as the cycle depends on regeneration of NAD+ and FAD from NADH and FADH2 1
• Chronic metabolic stress causes "dysmetabolism" where cells shift from efficient aerobic metabolism (Krebs cycle-based) to less efficient anaerobic glycolysis 1

Evolutionary and Metabolic Context

• The Krebs cycle represents an ancient metabolic pathway that evolved from bacterial origins, with most enzymes now encoded in the nuclear genome of eukaryotes following endosymbiotic gene transfer from the mitochondrial ancestor 6
• In contrast to the irreversible oxidative Krebs cycle, some photosynthetic bacteria use a "reverse Krebs cycle" (reductive carboxylic acid cycle) for CO2 fixation, demonstrating the pathway's fundamental importance and evolutionary flexibility 7