Regulation of mitochondrial respiratory chain biogenesis by estrogens/estrogen receptors and physiological, pathological and pharmacological implications

Abstract

There has been increasing evidence pointing to the mitochondrial respiratory chain (MRC) as a novel and important target for the actions of 17beta-estradiol (E(2)) and estrogen receptors (ER) in a number of cell types and tissues that have high demands for mitochondrial energy metabolism. This novel E(2)-mediated mitochondrial pathway involves the cooperation of both nuclear and mitochondrial ERalpha and ERbeta and their co-activators on the coordinate regulation of both nuclear DNA- and mitochondrial DNA-encoded genes for MRC proteins. In this paper, we have: 1) comprehensively reviewed studies that reveal a novel role of estrogens and ERs in the regulation of MRC biogenesis; 2) discussed their physiological, pathological and pharmacological implications in the control of cell proliferation and apoptosis in relation to estrogen-mediated carcinogenesis, anti-cancer drug resistance in human breast cancer cells, neuroprotection for Alzheimer's disease and Parkinson's disease in brain, cardiovascular protection in human heart and their beneficial effects in lens physiology related to cataract in the eye; and 3) pointed out new research directions to address the key questions in this important and newly emerging area. We also suggest a novel conceptual approach that will contribute to innovative regimens for the prevention or treatment of a wide variety of medical complications based on E(2)/ER-mediated MRC biogenesis pathway.

Fig. 1. MRC, H⁺-ATP Synthase and ANT

Schematic picture showing MRC complexes, H⁺-ATPase, and ANT. MRC: Mitochondrial respiratory chain; ANT: Adenosine Nucleotide Translocase.

Fig. 2. Human Mitochondrial Genome

The relative locations of genes encoding 13 MRC proteins for complex I (ND1, ND2, ND3, ND4, ND4L, ND5 and ND6); Complex III (cytb); Complex V (COX I, COX II and COX III) and H-ATP synthase (ATP6/8), two rRNAs (12S rRNA and 16S rRNA) and 22 tRNAs for specific amino acids indicated by the letters are shown. F: Phe, V: Val, L: Leu, I: Ile, Q: Gln; M: Met; W: Trp; A: Ala; N: Asn; C: Cys; Y: Tyr; S1: Ser, D: Asp; K: Lys; G: Gly; R: Arg; H: His; S2: Ser-2; L2: Leu-2; E: Glu; P: Pro; T: Thr. D-loop: Displace loop.

Fig. 3. Genetic and pharmacological evidence for MRC as Modulator of Apoptosis 3A. Correlation between MRC Composition and Apoptotic Response in mtDNA Mutant Cybrids

The RC components of the cybrids are depicted. WT cells have a full complement of RC complexes. ρ⁰ cells are missing complexes I, III, IV, and V. COX cells are missing complex IV and have reduced complex I (depicted as a smaller circle). CYTB cells are missing complex III and have reduced complex I. MERRF cells are missing complexes I, III, IV, and V, detectable by BN gel, but have some residual ATP hydrolytic complex V activity. NARP cells have all of the complexes in place, but have reduced amounts and activities. Normal response to apoptosis induction is represented by +, high response by +++, and low response by −. (Adapted from Kwong JQ et al. (153) with permission granted by J. Cell. Biology). 3B. Pharmacological Evidence for MRC as Modulator of Apoptosis: effects of specific inhibitors on individual complexes Induction of apoptosis by inhibitors specific for individual MRC complexes is shown. Inhibition of individual complex is represented by X; Normal response to apoptosis induction is represented by +.

Fig. 4. Proposed Pathway for Regulation of MRC Biogenesis by E₂/ERs and Physiological & Pathological Implications

This proposed pathway is simultaneously initiated and performed within nuclei and mitochondria. Inside the nuclei, the E₂-activated ERα and/or ERβ bind to the EREs and other relevant regulatory elements present in the promoter regions of several key transcription factors including NRF-1, NRF-2 and PGC-lα and activates their transcription. The increased expression of these transcriptional factors, in turn, stimulate the cooperate expression of nuclear genes encoding: A) a number of proteins factors involved in the replication, transcription and translations of mtDNA; B) the MRC proteins and MRC complex assembly proteins and C) several proteins of mitochondrial protein import machinery. These proteins are synthesized on cytosolic ribosomes, and imported into mitochondria via the mitochondrial protein import machinery. The enhanced expression of proteins of mitochondrial import machinery facilitates the mitochondrial import of proteins involved in the replication- transcription-translations of mtDNA, the nDNA-encoded MRC proteins and MRC complex assembly proteins, along with other mitochondrially localized proteins. Within mitochondria, the protein factors involved in mtDNA replication stimulate mtDNA replication and maintain/protection of mtDNA integrity. On the other hand, ERα and/or ERβ are imported into mitochondria. Once inside the mitochondria, E₂ enhances their binding to the mtEREs within the regulatory region (i.e. D-loop) of mtDNA, to form the active transcription complexes in association with the transcriptional factors (e.g. Tfam, TFBIM and TFBIIM) and stimulating mtDNA transcription. The enhanced levels of protein factors involved in translation of mitochondrial mRNAs stimulate the translation of thirteen mtRNAs encoding MRC proteins. Both the newly imported, nDNA-encoded MRC subunits and the newly synthesized, mtDNA-encided MRC protein subunits are increasingly assembled into individual MRC complexes and ATP synthase by the increased MRC complex assembly proteins, resulting in increased MRC biogenesis and functions. The consequences of these processes are the increased production of mitochondrial energy in form of ATP and MRC-derived ROS. NRF-1, NRF-2, PGC-lα and Sp1 are the master players involved in the regulation of the majority of proteins and important factors involved in almost all aspects of MRC protein biogenesis. E₂ and ERs act as the key “directors” for the entire pathway. The normal operation of this pathway is of physiological importance for the proper functions of a number of cell types and organs. Persistent over-stimulation or deficiency of E₂/ER-mediated MRC biogenesis and functions can cause alterations in mitochondrial functions, resulting in over-abundance or deficiency of ATP and ROS. The changes in ATP and ROS levels and abnormal mitochondrial functions can also trigger retrograde regulation (e.g. redox-sensitive regulation) of the expression of nuclear genes involved a wide variety of physiological processes including oxidative response signaling pathways, various kinase-mediated pathways, cell cycle-related pathways and cell growth/death-related pathways. The combination of these E₂/ER-mediated mitochondrial effects and the resulting retrograde regulation of expression of different types of nuclear genes have a number of physiological implications in different types of cells and organs. Persistent induction of these mitochondrial effects can exist in breast cells due to relatively higher levels of E₂ and ERs in these cells, leading to over-abundance of these effects, which may contribute to increased cell proliferation and inhibition of apoptosis as well as resistance to anti-cancer drugs. These effects are relevant to estrogen-mediated carcinogenesis in human breast. On the other hand, stimulation of MRC biogenesis/functions by E₂ and ERs are highly beneficial for providing the cells in brain, heart and the eye with sufficient MRC-derived energy for their proper functions. Maintenance of cell survival and inhibition of induced-apoptosis by E₂/ER-mdiated MRC biogenesis and functions in neurons in brain, cardiomyocytes in heart and lens cells in the eye confer significant protection against AD and PD, heart diseases and the eye diseases (e.g. cataract formation).