Review Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism ..., 2024, Spinelli et al.

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Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System
Spinelli, Sonia; Bruschi, Maurizio; Passalacqua, Mario; Guida, Lucrezia; Magnone, Mirko; Sturla, Laura; Zocchi, Elena

The orphan nuclear receptor ERRα is the most extensively researched member of the estrogen-related receptor family and holds a pivotal role in various functions associated with energy metabolism, especially in tissues characterized by high energy requirements, such as the heart, skeletal muscle, adipose tissue, kidney, and brain. Abscisic acid (ABA), traditionally acknowledged as a plant stress hormone, is detected and actively functions in organisms beyond the land plant kingdom, encompassing cyanobacteria, fungi, algae, protozoan parasites, lower Metazoa, and mammals. Its ancient, cross-kingdom role enables ABA and its signaling pathway to regulate cell responses to environmental stimuli in various organisms, such as marine sponges, higher plants, and humans.

Recent advancements in understanding the physiological function of ABA and its mammalian receptors in governing energy metabolism and mitochondrial function in myocytes, adipocytes, and neuronal cells suggest potential therapeutic applications for ABA in pre-diabetes, diabetes, and cardio-/neuroprotection. The ABA/LANCL1-2 hormone/receptor system emerges as a novel regulator of ERRα expression levels and transcriptional activity, mediated through the AMPK/SIRT1/PGC-1α axis. There exists a reciprocal feed-forward transcriptional relationship between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which may be leveraged using natural or synthetic LANCL agonists to enhance mitochondrial function across various clinical contexts.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

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The principal conclusions that can be drawn from the literature discussed in this review can be summarized as follows:

• Enhancing ERRα activity promotes mitochondrial health and protects against oxidative stress in several aerobic organs and tissues, particularly in the heart, skeletal muscle, brain, and kidney.

• Repressing ERRα activity is a means to undermine mitochondrial energy metabolism (supporting cell duplication) and cytoskeletal dynamics (allowing cell migration) in cancer cells.

• The ABA/LANCL1-2 hormone/receptor system emerges as a new controller of ERRα expression levels and transcriptional activity via the AMPK/SIRT1/PGC-1α axis.

• A reciprocal feed-forward transcriptional relationship exists between the LANCL proteins and transcriptional coactivators ERRα/PGC-1α, which could be exploited with natural or synthetic LANCL agonists to improve mitochondrial function in multiple clinical settings.

 

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See also —

New Insights into the LANCL2-ABA Binding Mode towards the Evaluation of New LANCL Agonists
Scarano, Naomi; Di Palma, Francesco; Origlia, Nicola; Musumeci, Francesca; Schenone, Silvia; Spinelli, Sonia; Passalacqua, Mario; Zocchi, Elena; Sturla, Laura; Cichero, Elena; Cavalli, Andrea

The lanthionine synthetase C-like (LANCL) proteins include LANCL2, which is expressed in the central nervous system (CNS) and in peripheral tissues. LANCL2 exhibits glutathionylation activity and is involved in the neutralization of reactive electrophiles. Several studies explored LANCL2 activation as a validated pharmacological target for diabetes and inflammatory bowel disease. In this context, LANCL2 was found to bind the natural product abscisic acid (ABA), whose pre-clinical effectiveness in different inflammatory diseases was reported in the literature.

More recently, LANCL2 attracted more attention as a valuable resource in the field of neurodegenerative disorders. ABA was found to regulate neuro-inflammation and synaptic plasticity to enhance learning and memory, exhibiting promising neuroprotective effects. Up until now, a limited number of LANCL2 ligands are known; among them, BT-11 is the only compound patented and investigated for its anti-inflammatory properties.

To guide the design of novel putative LANCL2 agonists, a computational study including molecular docking and long molecular dynamic (MD) simulations of both ABA and BT-11 was carried out. The results pointed out the main LANCL2 ligand chemical features towards the following virtual screening of a novel putative LANCL2 agonist (AR-42). Biochemical assays on rat H9c2 cardiomyocytes showed a similar, LANCL2-mediated stimulation by BT-11 and by AR-42 of the mitochondrial proton gradient and of the transcriptional activation of the AMPK/PGC-1α/Sirt1 axis, the master regulator of mitochondrial function, effects that are previously observed with ABA.

These results may allow the development of LANCL2 agonists for the treatment of mitochondrial dysfunction, a common feature of chronic and degenerative diseases.

Link | PDF (Pharmaceutics) [Open Access]