ERα in the Control of Mitochondrial Function and Metabolic Health

Decrements in metabolic health elevate disease risk, including type 2 diabetes, heart disease, and certain cancers. Thus, treatment strategies to combat metabolic dysfunction are needed. Reduced ESR1 (estrogen receptor, ERα) expression is observed in muscle from women, men, and animals presenting clinical features of the metabolic syndrome. Human studies of natural expression of ESR1 in metabolic tissues show that muscle expression of ESR1 is positively correlated with markers of metabolic health, including insulin sensitivity. Herein, we highlight the important impact of ERα on mitochondrial form and function and present how these actions of the receptor govern metabolic homeostasis. Studies identifying ERα-regulated pathways for disease prevention will lay the foundation for the design of novel therapeutics to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions. Impaired estrogen action is associated with metabolic dysfunction and insulin resistance in human subjects.Experimental deletion of Esr1 from muscle drives insulin resistance and increases adiposity in male and female mice compared with estrogen receptor (ER)α-replete animals.Mitochondria from muscle harboring an Esr1 deletion mutation are dysmorphic (enlarged and hyperfused) and dysfunctional, with a reduced oxidative capacity.RNA analyses show that the gene encoding the catalytic subunit of polymerase γ, Polg1, is markedly reduced in muscle-specific ERα knockout mice. Reduced Polg1 expression, due to reduced ERα binding to the Polg1 proximal promoter, blunts mitochondrial DNA replication and impairs mitochondrial dynamics and turnover by mitophagy, thereby promoting the retention of damaged mitochondria to the network.Abundant evidence suggests that the maintenance of ERα action is critical for preserving mitochondrial function and metabolic health.