Expression patterns of ERα66 and its novel variant isoform ERα36 in lactotroph pituitary adenomas and associations with clinicopathological characteristics

Pituitary - The regulatory effects of estradiol on pituitary homeostasis have been well documented. However, the expression patterns of ERα66 and ERα36 and their correlations with the...     

Distribution of estrogen receptors (ERα and ERβ) and androgen receptor in the testis of big fruit-eating bat Artibeus lituratus is cell- and stage-specific and increases during gonadal regression

The testis is a classical target for androgens, especially testosterone, acting via androgen receptor (AR). Alternatively, androgens can be aromatized to produce estrogens which act via specific receptors ERα and ERβ. Although estrogen action is essential for maintenance of male fertility, studies regarding the expression of ERα and ERβ in testis are restricted to a few species of rodent and domestic animals, but rarely in wild species. To our knowledge, there are no studies in Chiroptera species. Chiroptera represent one of the largest and most diversified orders of mammals, which possess several interesting reproductive features, including higher affinity of SHBG for estrogens than androgens. Therefore, we thought that bats would constitute a good model for investigation of the role of estrogens in the male. In this study, the distribution of ERα, ERβ and AR were evaluated in the testis of the big fruit-eating bat Artibeus lituratus and their levels were compared during reproductive and regressive periods. The results showed that ERα and AR were restricted to the somatic cells of the testis, whereas ERβ was widely distributed in both somatic and spermatogenic cells in a cellular and stage-specific fashion. We demonstrated for the first time by immunohistochemistry, and confirmed by Western blotting, that ERβ and AR increased during regression. The localization of ERα, ERβ and AR in a seasonal, cell and stage-specific fashion in the testis of A. lituratus suggests that these receptors may play important roles in testis function during reproductive and non-reproductive periods.     

A small molecule inhibitor of NFκB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis

Journal of Gastroenterology - The underlying molecular mechanism that leads to development of chronic pancreatitis remains elusive. The aim of this study is to understand the downstream...     

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

Estrogens are not only critical for sexual differentiation it is well-known for the role of 17β-estradiol (E2) in the adult brain modulating memory, learning, mood and acts as a neuroprotector. E2 exerts its actions through two classical receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The distribution of both receptors changes from one brain area to another, E2 being able to modulate their expression. Among the classical features of aging in humans, we find cognitive impairment, dementia, memory loss, etc. As estrogen levels change with age, especially in females, it is important to know the effects of low E2 levels on ERα distribution; results from previous studies are controversial regarding this issue. In the present work, we have studied the effects of long-term E2 depletion as well as the ones of E2 treatment on ERα brain distribution of ovariectomized rats along aging in the diencephalon and in the telencephalon. We have found that ovariectomy causes downregulation and affects subcellular localization of ERα expression during aging, meanwhile prolonged estrogen treatment produces upregulation and overexpression of the receptor levels. Our results support the idea of the region-specific neuroprotection mechanisms mediated by estradiol.     

Anxiolytic effects and neuroanatomical targets of estrogen receptor-β (ERβ) activation by a selective ERβ agonist in female mice

The dichotomous anxiogenic and anxiolytic properties of estrogens have been reported to be mediated by two distinct neural estrogen receptors (ER), ERα and ERβ, respectively. Using a combination of pharmacological and genetic approaches, we confirmed that the anxiolytic actions of estradiol are mediated by ERβ and extended and these observations to demonstrate the neuroanatomical targets involved in ERβ activation in these behavioral responses. We examined the effects of the biologically active S-enantiomer of diarylpropionitrile (S-DPN) on anxiety-related behavioral measures, the corresponding stress hormonal response to hypothalamo-pituitary-adrenal axis reactivity, and potential sites of neuronal activation in mutant female mice carrying a null mutation for ERβ gene (βERKO). S-DPN administration significantly reduced anxiety-like behaviors in the open field, light-dark exploration, and the elevated plus maze (EPM) in ovariectomized wild-type (WT) mice, but not in their βERKO littermates. Stress-induced corticosterone (CORT) and ACTH were also attenuated by S-DPN in the WT mice but not in the βERKO mice. Using c-fos induction after elevated plus maze, as a marker of stress-induced neuronal activation, we identified the anterodorsal medial amygdala and bed nucleus of the stria terminalis as the neuronal targets of S-DPN action. Both areas showed elevated c-fos mRNA expression with S-DPN treatment in the WT but not βERKO females. These studies provide compelling evidence for anxiolytic effects mediated by ERβ, and its neuroanatomical targets, that send or receive projections to/from the paraventricular nucleus, providing potential indirect mode of action for the control of hypothalamo-pituitary-adrenal axis function and behaviors.     

Modulation of ERα transcriptional activity by the orphan nuclear receptor ERRβ and evidence for differential effects of long- and short-form splice variants

Oestrogen receptor related proteins (ERRs) affect target gene expression without binding oestradiol. We investigated the functional activity of two splice variant isoforms of ERRβ (ERRβS [short], ERRβL [long]) expressed in human endometrium, where they are coexpressed with the oestrogen receptor alpha (ERα). Over-expression of ERRβL enhanced ERα-dependent ligand-induced activation of an ERE-luciferase reporter construct, altered the induction of c-myc mRNA and increased proliferation of Ishikawa cells whereas ERRβS was found to reduce these endpoints.     

Ratio of Circulating Estrogen Receptors Beta and Alpha (ERβ/ERα) Indicates Endoscopic Activity in Patients with Crohn’s Disease

Background

Data supporting a role of female hormones and/or their receptors in inflammatory bowel disease (IBD) are increasing, but most of them are derived from animal models. Estrogen receptors alpha (ERα) and beta (ERβ) participate in immune and inflammatory response, among a variety of biological processes. Their effects are antagonistic, and the net action of estrogens may depend on their relative proportions.

Aim

To determine the possible association between the balance of circulating ERβ and ERα (ERβ/ERα) and IBD risk and activity.

Methods

Serum samples from 145 patients with IBD (79 Crohn’s disease [CD] and 66 ulcerative colitis [UC]) and 39 controls were retrospectively studied. Circulating ERα and ERβ were measured by ELISA. Disease activities were assessed by clinical and endoscopic indices specific for CD and UC.

Results

Low values of ERβ/ERα ratio were directly associated with clinical (p = 0.019) and endoscopic (p = 0.002) disease activity. Further analyses by type of IBD confirmed a strong association between low ERβ/ERα ratio and CD clinical (p = 0.011) and endoscopic activity (p = 0.002). The receiver operating curve (ROC) analysis showed that an ERβ/ERα ratio under 0.85 was a good marker of CD endoscopic activity (area under the curve [AUC]: 0.84; p = 0.002; sensitivity: 70%; specificity: 91%). ERβ/ERα ratio was not useful to predict UC activity.

Conclusions

An ERβ/ERα ratio under 0.85 indicated CD endoscopic activity. The determination of serum ERβ/ERα might be a useful noninvasive screening tool for CD endoscopic activity.

     

Seasonal variation in estrogen receptor ERα, but not ERβ, androgen receptor and aromatase, in the efferent ductules and epididymis of the big fruit-eating bat Artibeus lituratus

The efferent ductules (ED) are a major target for estrogens, which act via the estrogen receptors ERα (ESR1) and ERβ (ESR2). ERα has been found in the ED of all species studied so far. However, in the epididymis (EP), the expression of ERα is controversial, as is data about the occurrence of aromatase in the epithelium lining the excurrent ducts. Therefore, to further investigate this estrogen-responsive system, we used a seasonal breeder, the Neotropical bat, Artibeus lituratus, in which testicular expression of androgen (AR) and estrogen (ER) receptors vary with reproductive phase. The localization of aromatase, ERα, ERβ and AR in the ED and EP of A. lituratus was investigated. The results showed that aromatase, AR and ERβ were distributed throughout the excurrent ducts and did not vary during the annual reproductive cycle. Conversely, ERα was detected primarily in the ED epithelium, had marked seasonal variation and was increased during regression, especially in the EP epithelium. The results suggest that ERα may be involved in preparing the male genital tract for recrudescence. Together, the data obtained under natural conditions emphasize that specific segments of the excurrent ducts downstream of the testis are the primary targets for estrogen action via ERα, which is similar to previous findings in animals lacking functional ERα.     

Interactions between IGF-I, estrogen receptor-α (ERα), and ERβ in regulating growth/apoptosis of MCF-7 human breast cancer cells

Understanding of the interactions between estradiol (E?) and IGF-I is still incomplete. Cell lines derived from the MCF-7 breast cancer cells were generated with suppressed expression of the IGF-I receptor (IGF-IR), termed IGF-IR.low cells, by stable transfection using small interfering RNA (siRNA) expression vector. Vector for control cells carried sequence generating noninterfering RNA. Concomitant with reduction in the IGF-IR levels, the IGF-IR.low cells also showed a reduction in estrogen receptor α (ERα) and progesterone receptor expressions, and an elevation in the expression of ERβ. The number of the IGF-IR.low cells was reduced in response to IGF-I and human GH plus epidermal growth factor, but E? did not cause an increase in the number of the IGF-IR.low cells compared to controls. The proliferation rate of IGF-IR.low cells was only reduced in response to E? compared to controls, whereas their basal and hormone-stimulated apoptosis rate was increased. Phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was increased in the IGF-IR.low cells after treatment with E?, without affecting control cells. Furthermore, phosphorylation of the tumor suppressor protein p53 was elevated in the IGF-IR.low cells compared to the controls. In conclusion, suppressing IGF-IR expression decreased the level of ERα but increased the level of ERβ. Overall growth rate of the IGF-IR.low cells was reduced mostly through an increase in apoptosis without affecting proliferation substantially. We hypothesize that a decreased ERα:ERβ ratio triggered a rapid phosphorylation of p38 MAPK, which in turn phosphorylated the p53 tumor suppressor and accelerated apoptosis rate.     

Aggressive Prostate Cancer Is Prevented in ERαKO Mice and Stimulated in ERβKO TRAMP Mice

Previous evidence suggests soy genistein may be protective against prostate cancer, but whether this protection involves an estrogen receptor (ER)-dependent mechanism is unknown. To test the hypothesis that phytoestrogens may act through ERα or ERβ to play a protective role against prostate cancer, we bred transgenic mice lacking functional ERα or ERβ with transgenic adenocarcinoma of mouse prostate (TRAMP) mice. Dietary genistein reduced the incidence of cancer in ER wild-type (WT)/transgenic adenocarcinoma of mouse prostate mice but not in ERα knockout (KO) or ERβKO mice. Cancer incidence was 70% in ERWT mice fed the control diet compared with 47% in ERWT mice fed low-dose genistein (300 mg/kg) and 32% on the high-dose genistein (750 mg/kg). Surprisingly, genistein only affected the well differentiated carcinoma (WDC) incidence but had no effect on poorly differentiated carcinoma (PDC). No dietary effects have been observed in either of the ERKO animals. We observed a very strong genotypic influence on PDC incidence, a protective effect in ERαKO (only 5% developed PDC), compared with 19% in the ERWT, and an increase in the incidence of PDC in ERβKO mice to 41%. Interestingly, immunohistochemical analysis showed ERα expression changing from nonnuclear in WDC to nuclear in PDC, with little change in ERβ location or expression. In conclusion, genistein is able to inhibit WDC in the presence of both ERs, but the effect of estrogen signaling on PDC is dominant over any dietary treatment, suggesting that improved differential targeting of ERα vs. ERβ would result in prevention of advanced prostate cancer.     

ER stress in rodent islets of Langerhans is concomitant with obesity and β-cell compensation but not with β-cell dysfunction and diabetes

Objective:

The objective of this study was to determine whether ER stress correlates with β-cell dysfunction in obesity-associated diabetes.

Methods:

Quantitative RT-PCR and western blot analysis were used to investigate changes in the expression of markers of ER stress, the unfolded protein response (UPR) and β-cell function in islets isolated from (1) non-diabetic Zucker obese (ZO) and obese female Zucker diabetic fatty (fZDF) rats compared with their lean littermates and from (2) high-fat-diet-fed fZDF rats (HF-fZDF), to induce diabetes, compared with age-matched non-diabetic obese fZDF rats.

Results:

Markers of an adaptive ER stress/UPR and β-cell function are elevated in islets isolated from ZO and fZDF rats compared with their lean littermates. In islets isolated from HF-fZDF rats, there was no significant change in the expression of markers of ER stress compared with age matched, obese, non-diabetic fZDF rats.

Conclusions:

These results provide evidence that obesity-induced activation of the UPR is an adaptive response for increasing the ER folding capacity to meet the increased demand for insulin. As ER stress is not exacerbated in high-fat-diet-induced diabetes, we suggest that failure of the islet to mount an effective adaptive UPR in response to an additional increase in insulin demand, rather than chronic ER stress, may ultimately lead to β-cell failure and hence diabetes.     

Estrogen receptor beta (ERβ) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm

Purpose Estrogen receptor (ER) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ER in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ER expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor (ER) and a pure antagonist of ER, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ER. The purpose of this study was to explore the expression of ER in astrocytic neoplasms.Methods ER expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I–IV) and in adjacent non-neoplastic brain tissue.Results Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ER expression paralleled the increase in tumor grade.Conclusions In as much as ER is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.     

AIB1 shows variation in interaction with ERβTAD and expression as a function of age in mouse brain

Estrogen mediates its multiple functions in the brain through the recruitment of a number of interacting proteins. In this paper, we report the identification of 160 kD interacting nuclear protein of estrogen receptor (ER)β-transactivation domain (TAD) as amplified in breast cancer 1(AIB1) by pull down assay, immunoblotting, far-western analysis and immunoprecipitation. Further we show the age dependent interaction and expression of AIB1 in the brain of young (6 weeks), adult (25 weeks) and old (70 weeks) AKR strain mice of both sexes. The immunoprecipitation data revealed higher interaction of AIB1 in young than adult and old male mice. In contrast, the interaction was low in young, increased in adult but decreased in old female. However, immunoblotting showed age related increase in the expression of AIB1 in both male and female mice. Further, the level of interaction of AIB1 with ERβTAD in young and old male was significantly higher than female of same age, whereas the expression of AIB1 in adult and old female was significantly higher than male of same age. These data suggest that such age dependent variation in the interaction of AIB1 with ERβTAD and its expression may be helpful to regulate estrogen-mediated gene functions during aging and neurodegenerative diseases.     

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

The stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM–ORAI function. However, little is known about proteins that organize ER–plasma membrane junctions for STIM–ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER–plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.Close contacts between the endoplasmic reticulum (ER) and the plasma membrane are the physical platform for stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) signaling, a prominent pathway for physiological calcium entry in mammalian cells (1–4). Release of calcium from ER stores, triggered by physiological stimuli, causes the ER membrane protein STIM1 to accumulate at ER–plasma membrane junctions and to gate plasma membrane ORAI1 channels. The junctions establish a 15- to 20-nm spacing between membranes that STIM1 can bridge to interact with ORAI1 (5). At the same time, the individual junctions define a specialized local geometry that contributes to shaping cellular calcium signaling (6, 7).Research into the cell biology of mammalian ER–plasma membrane junctions has benefited from parallels with the corresponding junctions in yeast. For example, the formation and maintenance of ER–plasma membrane junctions depends on tricalbins and other proteins in yeast cells (8–10) and in mammalian cells on the extended synaptotagmins (E-Syts), a family of three tricalbin homologs, and other unidentified proteins (11, 12). The insights from yeast extend to the mechanisms of cellular lipid metabolism and lipid transfer between the apposed bilayers that have been conserved from yeast cells to human cells (13–19). On the other hand, parallels with yeast are less informative about processes specific to mammalian cells, including the store-dependent calcium entry controlled by STIM–ORAI signaling.We previously completed a genome-wide RNAi screen to identify modulators of cellular calcium signaling (20). The finding that septin scaffold proteins in the vicinity of ER–plasma membrane junctions rearrange as an immediate response to ER calcium store depletion (20) underscored the importance of local membrane organization in calcium signaling and led us to focus on predicted transmembrane proteins that were identified in the screen. Here we show that transmembrane protein 110 (TMEM110) is an ER-resident membrane protein that supports the maintenance of ER–plasma membrane junctions competent for STIM–ORAI signaling and that has a key role in the local remodeling of the junctions during physiological signaling.     

Estrogen receptor (ER) β expression in oligodendrocytes is required for attenuation of clinical disease by an ERβ ligand

Treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand diarylpropionitrile (DPN) has been shown to have neuroprotective effects via stimulation of endogenous myelination. The direct cellular mechanisms underlying the effects of this ERβ ligand on the central nervous system are uncertain because different cell types in both the peripheral immune system and central nervous system express ERs. ERβ is the target molecule of DPN because DPN treatment fails to decrease EAE clinical symptoms in global ERβ-null mice. Here we investigated the potential role of ERβ expression in cells of oligodendrocyte (OL) lineage in ERβ ligand-mediated neuroprotection. To this end, we selectively deleted ERβ in OLs using the well-characterized Cre-loxP system for conditional gene knockout (CKO) in mice. The effects of this ERβ CKO on ERβ ligand-mediated neuroprotective effects in chronic EAE mice were investigated. ERβ CKO in OLs prevented DPN-induced decrease in EAE clinical disease. DPN treatment during EAE did not attenuate demyelination, only partially improved axon conduction, and did not activate the phosphatidylinositol 3-kinase/serine-threonine-specific protein kinase/mammalian target of rapamycin signaling pathway in ERβ CKO mice. However, DPN treatment significantly increased brain-derived neurotrophic factor levels in ERβ CKO mice. These findings demonstrate that signaling through ERβ in OLs is essential for the beneficial myelination effects of the ERβ ligand DPN in chronic EAE mice. Further, these findings have important implications for neuroprotective therapies that directly target OL survival and myelination.Multiple sclerosis (MS) is an inflammatory, demyelinating neurodegenerative disease characterized by physical, and often cognitive, deficits that can progress to severe debilitation. Although current MS treatments exist in the form of immunomodulatory or immunosuppressive agents, these treatments fail to halt disease progression and are not directly neuroprotective.Building on a wealth of research supporting a role for estrogens in neuroprotection, we have demonstrated that treatment of experimental autoimmune encephalomyelitis (EAE) mice with the estrogen receptor (ER) β ligand 2,3-bis(4-Hydroxyphenyl)-propionitrile (DPN) attenuates clinical disease, neurodegeneration, and axon demyelination and improves axon conduction (1–4). Notably, these effects were observed with both prophylactic and therapeutic treatment regimens, and they occurred in the presence of peripheral cytokine production and central nervous system (CNS) inflammation. Evidence of direct neuroprotection by an ERβ ligand is welcomed, because it circumvents ERα-mediated adverse effects of synthetic estrogens [i.e., increased breast and uterine endometrial growth in females and feminizing effects in males (5)].Because ERs are present in various cell types in the peripheral immune system and CNS, including cells of oligodendrocyte (OL) lineage, it is difficult to assess which cell type(s) mediate ERβ ligand-conferred neuroprotection (6). ERβ is the target molecule of DPN: DPN treatment fails to decrease EAE clinical symptoms in global ERβ-null mice (4). Although informative, such studies do not elucidate the cell type(s) on which DPN acts. We have recently demonstrated that therapeutic treatment with DPN increases mature OL numbers, remyelination-induced callosal conduction, and phosphorylated ERβ levels in OLs, and that it activates the phosphatidylinositol 3-kinase (PI3K)/serine-threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, a pathway implicated in OL survival, differentiation, and axon myelination (1, 7, 8). Taken together with the pronounced, functional improvement in endogenous myelination observed in DPN-treated chronic EAE mice, a direct effect on ERβ in OLs may mediate ERβ ligand-induced myelination/remyelination improvement and neuroprotection. To test this hypothesis, ERβ was selectively deleted from OLs using the well-characterized Cre-loxP recombination system for conditional gene knockout (CKO) in mice (9–12). The Olig2,ERβ CKO mice that resulted from crossing ERβ^flox/flox and Olig2-tva-Cre mice were viable and displayed normal behavior and gross CNS anatomy; hence, the effect of ERβ CKO in OLs on ERβ ligand-induced neuroprotection in chronic EAE mice was investigated. ERβ CKO in OLs prevented DPN-induced attenuation of clinical disease and demyelination and failed to activate the PI3K/Akt/mTOR signaling pathway. However, DPN treatment in Olig2,ERβ CKO mice partially improved axon conduction and reduced axonal loss and, as in WT mice, significantly increased BDNF levels. These findings reveal a direct action of the ERβ ligand DPN on ERβ in OLs in DPN-induced myelination/remyelination effects within a chronic mouse model of MS.     

Identification of estradiol/ERα-regulated genes in the mouse pituitary

Estrogen acts to prime the pituitary prior to the GnRH-induced LH surge by undiscovered mechanisms. This study aimed to identify the key components that mediate estrogen action in priming the pituitary. RNA extracted from the pituitaries of metestrous (low estrogen) and proestrus (high estrogen) stage mice, as well as from ovariectomized wild-type and estrogen receptor α (ERα) knockout mice treated with 17β-estradiol (E(2)) or vehicle, was used for gene expression microarray. Microarray data were then aggregated, built into a functional electronic database, and used for further characterization of E(2)/ERα-regulated genes. These data were used to compile a list of genes representing diverse biological pathways that are regulated by E(2) via an ERα-mediated pathway in the pituitary. This approach substantiates ERα regulation of membrane potential regulators and intracellular vesicle transporters, among others, but not the basic components of secretory machinery. Subsequent characterization of six selected genes (Cacna1a, Cacna1g, Cited1, Abep1, Opn3, and Kcne2) confirmed not only ERα dependency for their pituitary expression but also the significance of their expression in regulating GnRH-induced LH secretion. In conclusion, findings from this study suggest that estrogen primes the pituitary via ERα by equipping pituitary cells with critical cellular components that potentiate LH release on subsequent GnRH stimulations.     

A Mitofusin-2–dependent inactivating cleavage of Opa1 links changes in mitochondria cristae and ER contacts in the postprandial liver

Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria–ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria–ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.The last decade expanded our understanding of the importance of mitochondrial shape, position, and interorganellar interactions in the regulation of cell stress. For example, mitochondrial hyperfusion is a stress response that protects against cell death and autophagic degradation, whereas chronic stress triggers mitochondrial fragmentation and cell death. However, the in vivo implications of mitochondrial plasticity under normal physiological conditions are still largely unknown. The liver is a key organ responsible for nutrient sensing and the maintenance of whole-body energy homeostasis. Therefore, we considered the liver as a primary model to examine the changes in mitochondrial plasticity that accompanies physiological transitions in feeding and postprandial metabolism (1–4).The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionary conserved serine/threonine kinase that plays an important role in regulating metabolism and cell growth in response to anabolic signals (5). Studies indicate that mTORC1, which is activated by growth factors and amino acids, is a key sensor allowing cells and tissues to adapt their metabolism in response to the nutritional state (5). In the liver, it controls the activation of various metabolic processes including lipogenesis (6) and ketogenesis (3). Recent observations indicate that mTORC1 regulates mitochondrial biogenesis and metabolism (7, 8), but the underlying mechanisms remain to be determined.It has been established that the core machinery that governs mitochondrial shape and ultrastructure is essential. Indeed, genetic ablation of its components, which includes the outer mitochondrial membrane (OMM) fusion GTPase Mitofusin-1 (Mfn1) and Mfn2 (9) as well as the inner mitochondrial membrane (IMM) GTPase Optic atrophy 1 (Opa1) (10), is embryonic lethal. Similarly, the loss of the core fission GTPase Drp1 is also lethal (11). Tissue-specific deletions of these genes, including the liver (12, 13), are now emerging and lead to more complex phenotypes (14); however, these models will not inform us on the adaptive mitochondrial response to metabolic changes.Mitochondria cristae shape changes from the “orthodox” state, when oxidative phosphorylation is low, to a more “condensed” form in high respiratory conditions. The mechanisms that regulate these changes have emerged in cultured models (15), but have not been followed within tissues in vivo. The inner membrane GTPase Opa1 has been shown to regulate mitochondrial fusion and cristae architecture (16), where loss of Opa1 in cultured mouse embryonic or adult fibroblast cells compromised the function and assembly of the respiratory chain complexes. Further, recent studies have shown that Opa1 ablation in the liver leads to a loss of cristae (13). However, Opa1 function is complex and can also promote mitochondrial fragmentation (17). Upon mitochondrial dysfunction or depolarization, an inner membrane protease called Oma1 becomes activated, cleaving Opa1 into a short, soluble form that then promotes mitochondrial fragmentation (18, 19). Interestingly, mice lacking Oma1 are not embryonic lethal; rather, they show a metabolic phenotype where they become obese, accompanied by hepatic steatosis when placed on a high fat diet (20). This result is of critical importance because it hints at a major role of Opa1 proteolysis in metabolic adaptation and connects it to the emerging notion that central regulators of mitochondria mitochondria–ER tethering, like Mfn2, might also be central to this process (12). To shed light on this possibility, in this study we have used an in vivo mouse model to link changes in the structure of the mitochondria–ER contacts (MERCs) to that of the cristae. Our findings support a model where mitochondria adapt to the postprandial loss of mTORC1 signaling by activating an Mfn2-dependent degradation program of Opa1. Thus, mitochondria adapt to postprandial metabolic transitions by coupling the machineries that organize cristae architecture and MERC assembly, which were previously thought to operate independently of each other.