ATP citrate lyase improves mitochondrial function in skeletal muscle
Suman Das1, Frederic Morvan1, Benjamin Jourde1
1Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
Cell Metabolism
|June 4, 2015
Summary
Activating ATP citrate lyase (ACL) in skeletal muscle boosts mitochondrial function and ATP levels, counteracting muscle diseases. This pathway is crucial for muscle health and energy production.
Area of Science:
- Biochemistry
- Cellular Biology
- Muscle Physiology
Background:
- Mitochondrial dysfunction is linked to skeletal muscle disorders like cachexia, sarcopenia, and muscular dystrophies.
- ATP citrate lyase (ACL) is a key enzyme converting citrate to oxaloacetate and acetyl-CoA.
Purpose of the Study:
- To investigate the role of ACL activation in skeletal muscle mitochondrial function.
- To explore the IGF1/ACL signaling pathway's impact on cellular energy.
- To determine if ACL activation can improve mitochondrial health in muscle.
Main Methods:
- Investigated ACL activation in skeletal muscle cells (myotubes) and in vivo.
- Utilized IGF1 stimulation and AKT-dependent signaling pathways.
- Assessed mitochondrial function through cardiolipin levels, complex activity, oxygen consumption, and ATP production.
- Performed ACL knockdown experiments to confirm its role.
Main Results:
- IGF1 activates ACL via AKT, increasing cardiolipin and enhancing mitochondrial complex activity.
- ACL activation leads to increased oxygen consumption and ATP levels in skeletal muscle.
- ACL knockdown impairs mitochondrial function and blocks IGF1-induced benefits.
- In vivo studies show a correlation between ACL activity and elevated ATP levels.
Conclusions:
- The IGF1/ACL/cardiolipin pathway improves skeletal muscle mitochondrial function and ATP production.
- This pathway links anabolic signaling with the energy demands of muscle.
- Targeting ACL may offer therapeutic potential for mitochondrial dysfunction in muscle diseases.
Related Concept Videos
01:48ATP Synthase: Mechanism
19.0K
In animals, the mitochondrial F1F0 ATP synthase is the key protein that synthesizes ATP molecules through a complex catalytic mechanism. While the nuclear genome encodes the majority of ATP synthase subunits, the mitochondrial genome encodes some of the enzyme's most critical components. The formation of this multi-subunit enzyme is a complex multi-step process regulated at the level of transcription, translation, and assembly. Defects in one or more of these steps can result in decreased...
19.0K
01:24Muscle Recovery and Fatigue
5.0K
Muscle fatigue refers to the decline in a muscle's ability to maintain the force of contraction after prolonged activity. It primarily stems from changes within muscle fibers. Even before experiencing muscle fatigue, one may feel tired and have the urge to stop the activity. This response, known as central fatigue, occurs due to changes in the central nervous system, namely the brain and spinal cord. While there is no single mechanism that induces fatigue, it may serve as a protective...
5.0K
01:18ATP Synthase: Structure
17.9K
ATP synthase or ATPase is among the most conserved proteins found in bacteria, mammals, and plants. This enzyme can catalyze a forward reaction in response to the electrochemical gradient, producing ATP from ADP and inorganic phosphate. ATP synthase can also work in a reverse direction by hydrolyzing ATP and generating an electrochemical gradient. Different forms of ATP synthases have evolved special features to meet the specific demands of the cell. Based on their specific feature, ATP...
17.9K
02:36The Citric Acid Cycle
167.7K
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.
167.7K
01:28The Inner Mitochondrial Membrane
5.1K
The inner mitochondrial membrane is the primary site of ATP synthesis. The inner membrane domain that forms a smooth layer adjacent to the outer membrane is called the inner boundary membrane. This domain contains membrane transporters that drive metabolites in and out of the mitochondria. In contrast, the inner membrane network that invaginates into the matrix space is called the cristae membrane. This domain accounts for principle mitochondrial function as it accommodates the protein...
5.1K
01:19Translocation of Proteins into the Mitochondria
13.8K
Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
13.8K