From the Guidelines
The Krebs cycle plays a crucial role in cellular respiration, generating energy by oxidizing acetyl-CoA derived from carbohydrates, fats, and proteins, and its dysfunction is implicated in various clinical conditions, including diabetes, cancer, and neurodegenerative diseases. The Krebs cycle, also known as the citric acid cycle or TCA cycle, is a central metabolic pathway that occurs in the mitochondrial matrix and serves as the final common pathway for the oxidation of fuel molecules, producing NADH and FADH2 that transfer electrons to the electron transport chain for ATP synthesis 1. In clinical medicine, the Krebs cycle has significant relevance in several conditions, including diabetes management, where understanding the cycle helps explain metabolic derangements, as insulin resistance affects the efficiency of the pathway 1.
- The cycle is targeted in cancer therapy since many tumors show altered TCA cycle activity, with drugs like CPI-613 designed to disrupt cancer cell metabolism.
- Defects in enzymes of the cycle can cause rare metabolic disorders like fumarase deficiency, which leads to neurological impairments and developmental delays.
- During ischemic events like heart attacks or strokes, disruption of the cycle contributes to tissue damage through energy depletion and oxidative stress, as highlighted in a study on the diverse roles of mitochondria in ischemic stroke 1.
- The cycle also plays a role in neurodegenerative diseases, where mitochondrial dysfunction is increasingly recognized as a pathological factor.
- Clinicians use biomarkers related to the cycle, such as succinate and fumarate levels, to diagnose certain conditions and monitor metabolic health.
The significance of the Krebs cycle in clinical medicine is further emphasized by its role in mitochondrial function and dynamics, which is crucial for maintaining cellular homeostasis and preventing disease 1. Understanding the Krebs cycle and its implications in various clinical conditions can inform the development of new therapeutic regimens and improve patient outcomes. Therefore, it is essential to consider the Krebs cycle in the diagnosis and management of various diseases, including diabetes, cancer, and neurodegenerative disorders.
From the Research
Role of the Krebs Cycle in Cellular Respiration
- The Krebs cycle, also known as the Citric Acid Cycle, is an amphibolic pathway operating in the mitochondrial matrix of all eukaryotic organisms 2.
- It plays a central role in energy production and anabolic processes, participating in key events such as the oxidation of acetate to yield reduction equivalents to the respiratory chain to make ATP 3.
- The Krebs cycle is crucial for the biosynthetic and bioenergetic requirements of the cell, and its rewiring in response to proinflammatory stimuli supports the effector functions of macrophages and dendritic cells 2.
Significance in Clinical Medicine
- Mitochondrial function impairment in several diseases, especially those that occur with neurodegeneration, highlights the importance of understanding the regulation of the Krebs cycle 4.
- The Krebs cycle has been implicated in the regulation of cytokine production and the inflammatory response, with its intermediates acting as signalling molecules and immunomodulators 2.
- The connection between mitochondria, metabolism, and stem cell fate suggests that understanding the crosstalk between mitochondria and cell fate is critical for the development of novel strategies to improve the treatment of degenerative diseases 5.
Regulation and Structure of the Krebs Cycle
- The Krebs cycle is regulated by the activation/deactivation of protein kinases and phosphatases, and signaling upon activation of G protein-coupled receptors (GPCRs) in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle 4.
- The structure of the Krebs cycle metabolon has been investigated using cross-linking and mass spectrometry, revealing substrate channeling and the formation of electrostatic channels upon protein-protein association 6.
- The design of the Krebs cycle as it occurs in living cells is the best chemical solution to oxidize acetate and yield reduction equivalents to the respiratory chain to make ATP, demonstrating the role of opportunism in molecular evolution 3.