Related Experiment Video
Updated: Jun 16, 2026
08:12
Measurement of Mitochondrial Respiration in Human and Mouse Skeletal Muscle Fibers by High-Resolution Respirometry
Published on: October 4, 2024
Urea cycle regulation by mitochondrial sirtuin, SIRT5.
Takashi Nakagawa1, Leonard Guarente
1Paul F. Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Aging
|February 17, 2010
Summary
Mitochondrial sirtuin 5 (SIRT5) activates carbamoyl phosphate synthetase 1 (CPS1), a key urea cycle enzyme. SIRT5 deficiency impairs metabolic adaptation to fasting and high-protein diets, causing hyperammonemia.
Area of Science:
- Biochemistry
- Metabolic regulation
- Mitochondrial function
Background:
- Mammalian sirtuins are NAD+-dependent enzymes involved in aging, metabolism, and disease.
- Sirtuins play critical roles in cellular regulation, including metabolic adaptation.
- The specific roles of SIRT5 in metabolic pathways are still being elucidated.
Purpose of the Study:
- To investigate the role of SIRT5 in urea cycle regulation.
- To determine the mechanism by which SIRT5 affects carbamoyl phosphate synthetase 1 (CPS1) activity.
- To explore the impact of SIRT5 deficiency on metabolic adaptation to physiological challenges.
Main Methods:
- Mitochondrial isolation and biochemical assays to measure enzyme activity.
- Western blotting and mass spectrometry to assess protein modification (acetylation).
- Analysis of SIRT5-deficient mouse models under various dietary conditions (fasting, high-protein diet, calorie restriction).
Main Results:
- SIRT5 was localized to the mitochondrial matrix.
- SIRT5 directly deacetylated and activated CPS1, a rate-limiting enzyme in the urea cycle.
- SIRT5-deficient mice exhibited impaired CPS1 activation and hyperammonemia during fasting, high-protein diet, or calorie restriction.
- These findings highlight SIRT5's crucial role in metabolic adaptation.
Conclusions:
- SIRT5 is a key regulator of the urea cycle through CPS1 deacetylation.
- SIRT5 plays an emerging role in metabolic adaptation to nutritional challenges.
- Targeting SIRT5 may offer therapeutic potential for metabolic disorders related to ammonia detoxification.
Related Concept Videos
01:23Urea Cycle
The urea cycle describes how liver cells convert ammonia to urea. Ammonia is a toxic waste product of protein catabolism. Land animals must convert ammonia into the less toxic urea which can be safely eliminated by the kidneys through urine. Marine animals excrete ammonia directly, and the surrounding water dilutes the ammonia to safe levels.
01:28The Citric Acid Cycle: Output
The citric acid cycle is termed an amphibolic pathway as it operates both anabolically and catabolically. The cyclic reactions balance the flux of the substrates to provide an optimal concentration of NADH and ATP to the cell.
Regulation of Citric Acid Cycle
The citric acid cycle is regulated in several ways, including feedback inhibition, regulation of enzyme activities, and associated anaplerotic or cataplerotic pathways.
The primary substrate of the TCA cycle—acetyl CoA—is produced by the...
Regulation of Citric Acid Cycle
The citric acid cycle is regulated in several ways, including feedback inhibition, regulation of enzyme activities, and associated anaplerotic or cataplerotic pathways.
The primary substrate of the TCA cycle—acetyl CoA—is produced by the...
02:36The Citric Acid Cycle
The citric acid cycle, also known as the Krebs cycle or TCA cycle, consists of several energy-generating reactions that yield one ATP molecule, three NADH molecules, one FADH2 molecule, and two CO2 molecules.
01:26Respiration Pathways
Cellular respiration is a fundamental metabolic process that enables organisms to generate energy from organic molecules. One of its central pathways is the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, which plays a crucial role in energy production and biosynthetic processes.Conversion of Pyruvate to Acetyl-CoAThe pyruvate generated from glycolysis undergoes oxidative decarboxylation by the pyruvate dehydrogenase complex, producing acetyl-CoA, one molecule of NADH, and one...
01:37Mitochondria
Mitochondria are eukaryotic cellular organelles that are known to produce energy through a process called oxidative phosphorylation. Besides their primary function, mitochondria are involved in various cellular processes, including cell growth, differentiation, signaling, metabolism, and senescence. Age-related changes cause a decline in mitochondrial quality and integrity due to increased mitochondrial mutations and oxidative damage. Thus, aging can severely impact mitochondrial functions,...
01:15Pyruvate Oxidation
After glycolysis, the charged pyruvate molecules enter the mitochondria via active transport and undergo three enzymatic reactions. These reactions ensure that pyruvate can enter the next metabolic pathway so that energy stored in the pyruvate molecules can be harnessed by the cells.
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...
First, the enzyme pyruvate dehydrogenase removes the carboxyl group from pyruvate and releases it as carbon dioxide. The stripped molecule is then oxidized and releases electrons, which are then picked up by NAD+...