Mitochondrial and sex steroid hormone crosstalk during aging

Abstract

Decline in circulating sex steroid hormones accompanies several age-associated pathologies which may influence human healthspan. Mitochondria play important roles in biosynthesis of sex steroid hormones, and these hormones can also regulate mitochondrial function. Understanding the cross talk between mitochondria and sex steroid hormones may provide insights into the pathologies associated with aging. The aim of this review is to summarize the current knowledge regarding the interplay between mitochondria and sex steroid hormones during the aging process. The review describes the effect of mitochondria on sex steroid hormone production in the gonads, and then enumerates the contribution of sex steroid hormones on mitochondrial function in hormone responsive cells. Decline in sex steroid hormones and accumulation of mitochondrial damage may create a positive feedback loop that contributes to the progressive degeneration in tissue function during aging. The review further speculates whether regulation between mitochondrial function and sex steroid hormone action can potentially influence healthspan.

Figure 1

Molecular targets of estrogen in regulating mitochondrial function. 1. Estrogen binds to nuclear estrogen receptors (ERα and ERβ) to directly regulate tissue-specific expression of genes necessary for cellular function. 2. Estrogen binds to nuclear ERs and regulates expression of mitochondrial genes by promoting gene expression of transcription factor NRF1 and enhancing transcriptional activity of PGC1α. 3. Estrogen binds to membrane ERs and activates signaling cascades that protect mitochondria from oxidative damage. 4. Estrogen binds to mitochondrial ERs and limits ROS generation in the mitochondria. 5. Estrogen binds to mitochondrial ERs and regulates transcription of mitochondrial-encoded mitochondrial genes.

Figure 2

Mitochondria and sex steroid hormones during aging. Mitochondria produce sex steroid hormones in the gonads through initial conversion of cholesterol to pregnenolone. Sex steroid hormones improve and/or maintain mitochondrial function in hormone responsive cells by regulating: 1. gene expression of nuclear-encoded mitochondrial proteins, 2. gene expression of mitochondrial-encoded mitochondrial proteins, and/or 3. activity of mitochondrial proteins. Increased oxidative stress during aging damages gonadal cells and/or impair steroidogenesis. Decline in sex steroid hormone biosynthesis during aging compromises mitochondrial function in hormone responsive tissues and contribute to age-related pathologies.