ATP Citrate Lyase Improves Mitochondrial Function in Skeletal Muscle
Open accessAbstract
Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT-dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP.
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The anabolic action of IGF1 requires the activity of ATP citrate lyase, which is phosphorylated and activated by AKT, resulting in improved mitochondrial respiration and ATP production.
“For instance, the anabolic action of IGF1 requires the activity of ATP citrate lyase (ACL), a cytosolic enzyme that catalyzes the conversion of mitochondrial-derived citrate into oxaloacetate and acetyl-CoA. Indeed, ACL is phosphorylated and activated by AKT resulting in an improvement of mitochondrial respiration and ATP production34.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [34]
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- Authors
- Das, S., Morvan, F., Jourde, B., Meier, V., Kahle, P., Brebbia, P., Toussaint, G., Glass, D. J., & Fornaro, M.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Glass, David J.
- Fornaro, Mara
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 21
- Issue
- 6
- Pages
- 868-876
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1538288223
- Cited by
- 91
- References
- 37
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 16 · 2023: 4 · 2022: 8 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 5 · 2017: 10 · 2016: 7 · 2015: 3
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- ATP citrate lyase, mitochondrial function, skeletal muscle, IGF-1 signaling, Akt, cardiolipin, mitochondrial supercomplexes, mitochondrial complex activity, oxygen consumption, ATP levels, mitochondrial dysfunction, cachexia, sarcopenia, muscular dystrophy
- MeSH terms
- Adenosine Triphosphate, ATP Citrate (pro-S)-Lyase, Cardiolipins, Humans, Insulin-Like Growth Factor I, Mitochondria, Muscle, Oxygen Consumption, Signal Transduction, Muscle Fibers, Skeletal, Citric Acid
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