Estrogen actions on mitochondria--physiological and pathological implications

Abstract

Estrogens are potent neuroprotective hormones and mitochondria are the site of cellular life-death decisions. As such, it is not surprising that we and others have shown that estrogens have remarkable effects on mitochondrial function. Herein we provide evidence for a primary effect of estrogens on mitochondrial function, achieved in part by the import of estrogen receptor beta (ERbeta) into the mitochondria where it mediates a number of estrogen actions on this vital organelle. ERbeta is imported into the mitochondria, through tethering to cytosolic chaperone protein and/or through direct interaction with mitochondrial import proteins. In the mitochondria, ERbeta can affect transcription of critical mitochondrial genes through the interaction with estrogen response elements (ERE) or through protein-protein interactions with mitochondrially imported transcription factors. The potent effects of estrogens on mitochondrial function, particularly during mitochondrial stress, argues for a role of estrogens in the treatment of mitochondrial defects in chronic neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) and more acute conditions of mitochondrial compromise, like cerebral ischemia and traumatic brain injury.

Figure 1. Tom20/22 and Tom70 receptors potential targeting of ERβ

A simplistic diagram of potential ERβ mitochondrial import through Tom receptor mediated activity. The Tom complex can recognize protein such as ERβ through two major receptor transport pathways, Tom20/Tom22 or Tom70. Tom20 with Tom22 can recognize a LXXLL presequences available in ligand bound ERβ (N-terminal or internal), then bind and transport ERβ across the outer membrane to the inner membrane or TIM complex. Alternatively, unliganded ERβ can be recognized by Tom70 through its chaparone complex, Hsp90/70. Hsp90 and Hsp70 can target proteins without a presequence by docking to tetraticopeptide repeat motifs (TRP) of Tom20 before ultimate transport to the TIM complex.

Figure 2. The mitochondrial distribution of ERβ shows co-localization with Tom20 and/or Hsp90

Dual immunofluorescent staining was performed in HT22 cells using mitotracker with either anti-ERβ, Tom20, or Hsp90. Fluorescent microscopy of HT22 cells stained for anti-Tom20, Hsp90 and/or ERβ also indicated that both Tom20 and Hsp90 associated with each other and with ERβ at the mitochondria.