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Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling.

Packer L, Cadenas E - J Clin Biochem Nutr (2010)

Bottom Line: The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status.Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors.This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The role of R-α-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status. Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors. This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis. The effects of lipoic acid on the neuronal energy-redox axis are largely reviewed in terms of their outcomes for aging and age-related neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

AMPK-dependent transcriptional pathway for PGC-1a activation.
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Related In: Results  -  Collection


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Figure 6: AMPK-dependent transcriptional pathway for PGC-1a activation.

Mentions: AMP-activated protein kinase (AMPK) is a sensitive cellular energy sensor(56) that supports ATP-generating catabolic pathways and decreases ATP-consuming anabolic processes by post-translational modifications and modulation of gene transcription (Fig. 6). AMPK consists of a catalytic (α) and two regulatory (β and γ) subunits, the γ subunit being the center of allosteric regulation (stimulated by AMP). Enzyme activation requires phosphorylation of a threonine residue by LKB1 or elevation of intracellular Ca++ via CaMKK. The effects of lipoic acid on AMPK differ depending on whether its action is on peripheral tissues or the hypothalamus(4) (AMPK in hypothalamic neurons integrates signals related to body’s energy metabolism). The different roles of AMPK in neurons have been critically reviewed:(57) depending on the experimental model, AMPK may function in a neuroprotective role or be harmful for neuronal survival or act as an autophagy mediator. AMPK is involved in transcriptional pathways that control mitochondrial function through PGC-1α.(58) The phosphorylation of PGC-1α protein(59) by AMPK at Thr177 and Ser538 appears to be a requirement for the induction of the PGC-1α promoter. Also, activation of AMPK was shown to enhance NAD+ levels in muscle cells and induce Sirt1-mediated PGC-1α deacetylation; apparently, PGC1α phosphorylation by AMPK facilitates the subsequent deacetylation by Sirt1.(60) The energy status of the cell is also related to activity of sirtuins,(61) which—among others—can deacetylase PGC-1α, by means of which Sirt1 controls mitochondrial biogenesis and function.


Lipoic acid: energy metabolism and redox regulation of transcription and cell signaling.

Packer L, Cadenas E - J Clin Biochem Nutr (2010)

AMPK-dependent transcriptional pathway for PGC-1a activation.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3022059&req=5

Figure 6: AMPK-dependent transcriptional pathway for PGC-1a activation.
Mentions: AMP-activated protein kinase (AMPK) is a sensitive cellular energy sensor(56) that supports ATP-generating catabolic pathways and decreases ATP-consuming anabolic processes by post-translational modifications and modulation of gene transcription (Fig. 6). AMPK consists of a catalytic (α) and two regulatory (β and γ) subunits, the γ subunit being the center of allosteric regulation (stimulated by AMP). Enzyme activation requires phosphorylation of a threonine residue by LKB1 or elevation of intracellular Ca++ via CaMKK. The effects of lipoic acid on AMPK differ depending on whether its action is on peripheral tissues or the hypothalamus(4) (AMPK in hypothalamic neurons integrates signals related to body’s energy metabolism). The different roles of AMPK in neurons have been critically reviewed:(57) depending on the experimental model, AMPK may function in a neuroprotective role or be harmful for neuronal survival or act as an autophagy mediator. AMPK is involved in transcriptional pathways that control mitochondrial function through PGC-1α.(58) The phosphorylation of PGC-1α protein(59) by AMPK at Thr177 and Ser538 appears to be a requirement for the induction of the PGC-1α promoter. Also, activation of AMPK was shown to enhance NAD+ levels in muscle cells and induce Sirt1-mediated PGC-1α deacetylation; apparently, PGC1α phosphorylation by AMPK facilitates the subsequent deacetylation by Sirt1.(60) The energy status of the cell is also related to activity of sirtuins,(61) which—among others—can deacetylase PGC-1α, by means of which Sirt1 controls mitochondrial biogenesis and function.

Bottom Line: The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status.Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors.This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis.

View Article: PubMed Central - PubMed

Affiliation: Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.

ABSTRACT
The role of R-α-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechanistically viewed in terms of thiol/disulfide exchange reactions that modulate the environment's redox and energy status. Lipoic acid-driven thiol/disulfide exchange reactions appear critical for the modulation of proteins involved in cell signaling and transcription factors. This review emphasizes the effects of lipoic acid on PI3K and AMPK signaling and related transcriptional pathways that are integrated by PGC-1α, a critical regulator of energy homoestasis. The effects of lipoic acid on the neuronal energy-redox axis are largely reviewed in terms of their outcomes for aging and age-related neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus