The Krebs Cycle (Citric Acid Cycle)
The Krebs cycle is a central mitochondrial metabolic pathway that oxidizes acetyl-CoA derived from carbohydrates, fats, and proteins to generate ATP, NADH, and FADH2 for cellular energy production, while also providing biosynthetic precursors for macromolecule synthesis. 1
Core Function and Mechanism
The tricarboxylic acid (TCA) cycle, also known as the Krebs cycle or citric acid cycle, serves as the final common pathway in aerobic metabolism for nutrient oxidation 2, 1. This cycle operates in the mitochondrial matrix and performs several critical functions:
- Energy production: The cycle oxidizes nutrients to support cellular bioenergetics, generating NADH for ATP synthesis through oxidative phosphorylation 3
- Biosynthetic precursor supply: Functions as an amphoteric pathway, contributing both to catabolic degradation and anaplerotic reactions that supply precursors for macromolecule biosynthesis 3
- Metabolic flexibility: The cycle exhibits dynamic behavior with products that can be co-opted in various physiological and pathological states 1
Key Metabolic Properties
Carbohydrates (as glucose and pyruvate) provide three unique properties for the Krebs cycle: (i) they can provide ATP in the absence of oxygen; (ii) they offer higher oxidative efficiency (ATP/oxygen ratio); and (iii) they allow an anaplerotic flux providing Krebs-cycle intermediates and other compounds 2.
The cycle requires a mandatory supply of pyruvate to the mitochondria, though the source is flexible—whether from glucose, lactate, or alanine does not affect the metabolic outcome 2.
Critical Regulatory Points
The oxoglutarate dehydrogenase complex (OGDHc) represents a highly regulated enzyme in the TCA cycle that converts α-ketoglutarate to succinyl-CoA while generating NADH 3. This step:
- Collaborates with glutaminolysis at an intersectional point to govern α-ketoglutarate levels 3
- Functions as a critical redox sensor in mitochondria due to its sensitivity to peroxides 3
- Mediates activation of several antioxidant pathways 3
Metabolic Integration
The Krebs cycle connects tightly to protein metabolism, as the pool of amino acids released from protein breakdown represents a major source of endogenous substrates, along with glycerol from triglyceride hydrolysis 2. Conversely, carbohydrate metabolism provides the carbon skeleton required for non-essential amino acid synthesis 2.
Fatty acids cannot serve as adequate precursors for carbohydrate synthesis because there is no anaplerotic flux from acetyl-CoA, unlike pyruvate 2.
Metabolic Flux Analysis
Modern understanding reveals that the TCA cycle can operate bidirectionally in certain contexts:
- Forward (oxidative) direction: Glutamine metabolism via glutaminolysis produces M+4-labeled succinate, fumarate, malate, and oxaloacetate 2
- Reverse (reductive) direction: Reductive carboxylation converts glutamine to α-ketoglutarate, then to citrate (catalyzed by isocitrate dehydrogenases), and finally to acetyl-CoA for lipogenesis 2
This flexibility allows cells to adapt the cycle configuration to meet distinct metabolic requirements 1.
Clinical Relevance
Dysregulation of Krebs cycle enzymes impairs cellular redox homeostasis and disturbs substrate fluxes, leading to buildup of oncometabolites in cancer pathogenesis 3. Succinate, a Krebs cycle intermediate, can function as an extracellular signaling molecule through GPR91 receptors, affecting blood pressure regulation, lipolysis inhibition, and cardiac hypertrophy 4.
The marathon runner's metabolism exemplifies optimal Krebs cycle function—energy is provided primarily through fatty acid oxidation via the Krebs cycle in a balanced steady state with no oxygen debt 2.