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

Abstract

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.

Keywords: AMPK/PGC-1α/SIRT1; BAT; biogenesis and proton gradient; cardioprotection; energy production; kidney; mitochondrial function; neurodegeneration; oxidative stress; oxphos uncoupling; skeletal muscle.

Figure 1

The protein architecture of the three estrogen-related receptors (ERRs). ERRs consist of six conserved regions (A/B, C, D, and E/F domains). The number between the two receptors indicates the sequence identity of the corresponding domain between different receptors.

Figure 2

The LANCL/ERRα/PGC-1α axis: uncoupling the yin and yang of mitochondrial function. Several feed-forward mechanisms concur in maintaining the LANCL1-2/AMPK/SIRT1/ERRα/PGC-1α axis active once “started”. AMPK stimulates Nampt activity and NAD synthesis, consequently increasing SIRT1 activity; AMPK and SIRT1 post-translationally modify and activate PGC-1α; LANCL1/2 expression levels upregulate the expression of AMPK, ERRα, PGC-1α, and ERRα, which, in turn, control LANCL1/2 expression [68,70,72]. This signaling axis stimulates mitochondrial biogenesis and oxphos activity and upregulates the cell’s ability to cope with increased oxidative stress at the same time, which is linked to a higher respiration capacity. Environmental stresses, such as variations in nutrient, oxygen, temperature, or cell energy status, and the stress hormone ABA, trigger the activation of this highly conserved signaling axis. This axis, in turn, exerts transcriptional control over hundreds of genes involved in key cell processes in tissues and organs with high energy demands, resulting in increased mitochondrial energy production and antioxidant defense. These responses affect the whole-body energy balance; thus, agonists of this signaling axis could be used not only to improve organ-specific diseases but also to ameliorate systemic conditions with multi-organ failures, such as diabetes and aging.