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Cell Metab. 2015 Jun 2;21(6):868-76. doi: 10.1016/j.cmet.2015.05.006.

ATP citrate lyase improves mitochondrial function in skeletal muscle.

Author information

1
Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland.
2
Novartis Institutes for Biomedical Research, 100 Technology Square, Cambridge, MA 02139, USA. Electronic address: david.glass@novartis.com.
3
Novartis Institutes for Biomedical Research, Forum 1, Novartis Campus, 4056 Basel, Switzerland. Electronic address: mara.fornaro@novartis.com.

Abstract

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.

PMID:
26039450
DOI:
10.1016/j.cmet.2015.05.006
[Indexed for MEDLINE]
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