The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis

Castillo, Ana Fernanda; Orlando, Ulises Daniel; Helfenberger, Katia Estefanía; Poderoso, Cecilia; Podestá, Ernesto J.

doi:10.1016/j.mce.2014.12.011

Cited by 51 publications

(41 citation statements)

References 98 publications

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“…Gauging the effect of sex and sex hormones on physiology is complex due to conversion between hormone classes, changing levels of bioactivity, steroid metabolism into other bioactive compounds, and hormone synthesis in nonclassical steroidogenic tissues. In target cells, changes in hormone-receptor isotype abundance or localization (91,294,325,355), variations in activity of enzymes responsible for sex hormone synthesis (47,202,253), interactions with genomic and nongenomic cofactors (265), additive or opposing effects of multiple hormones or receptors (142,191), and epigenetic phenomena (219) can drastically alter the downstream effect of hormone-receptor binding. At a broader level, the expression and activity of sex steroid receptors, as well as hormone-metabolizing enzymes, may be affected by sex, age, diet, environmental exposures, fluctuations in endogenous sex hormone levels (e.g., menstrual cycle and menopause), and various disease states (reviewed in Ref.…”

Section: Overview Of Sex Hormone Synthesis and Metabolismmentioning

confidence: 99%

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Hester

Ventetuolo

Lahm

2019

Comprehensive Physiology

110

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Pulmonary hypertension (PH) encompasses a syndrome of diseases that are characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling and that frequently lead to right ventricular (RV) failure and death. Several types of PH exhibit sexually dimorphic features in disease penetrance, presentation, and progression. Most sexually dimorphic features in PH have been described in pulmonary arterial hypertension (PAH), a devastating and progressive pulmonary vasculopathy with a 3-year survival rate <60%. While patient registries show that women are more susceptible to development of PAH, female PAH patients display better RV function and increased survival compared to their male counterparts, a phenomenon referred to as the "estrogen paradox" or "estrogen puzzle" of PAH. Recent advances in the field have demonstrated that multiple sex hormones, receptors, and metabolites play a role in the estrogen puzzle and that the effects of hormone signaling may be time and compartment specific. While the underlying physiological mechanisms are complex, unraveling the estrogen puzzle may reveal novel therapeutic strategies to treat and reverse the effects of PAH/PH. In this article, we (i) review PH classification and pathophysiology; (ii) discuss sex/gender differences observed in patients and animal models; (iii) review sex hormone synthesis and metabolism; (iv) review in detail the scientific literature of sex hormone signaling in PAH/PH, particularly estrogen-, testosterone-, progesterone-, and dehydroepiandrosterone (DHEA)-mediated effects in the pulmonary vasculature and RV; (v) discuss hormone-independent variables contributing to sexually dimorphic disease presentation; and (vi) identify knowledge gaps and pathways forward.

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Section: Overview Of Sex Hormone Synthesis and Metabolismmentioning

confidence: 99%

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Hester

Ventetuolo

Lahm

2019

Comprehensive Physiology

110

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“…Phosphorylation of TRAP1 impairs succinate dehydrogenase (SDH) leading to the accumulation of succinate and tumor progression . The most widely recognized metabolic interaction is between ERK1/2 and the steroidogenic acute regulatory protein (StAR) . ERK1/2 phosphorylates StAR on Ser 232, which stabilizes the protein in mitochondria and sustains steroid synthesis.…”

Section: Mitogen‐activated Protein Kinases (Mapks)mentioning

confidence: 99%

Phosphoregulation on mitochondria: Integration of cell and organelle responses

2019

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Mitochondria are highly integrated organelles that are crucial to cell adaptation and mitigating adverse physiology. Recent studies demonstrate that fundamental signal transduction pathways incorporate mitochondrial substrates into their biological programs. Reversible phosphorylation is emerging as a useful mechanism to modulate mitochondrial function in accordance with cellular changes. Critical serine/threonine protein kinases, such as the c‐Jun N‐terminal kinase (JNK), protein kinase A (PKA), PTEN‐induced kinase‐1 (PINK1), and AMP‐dependent protein kinase (AMPK), readily translocate to the outer mitochondrial membrane (OMM), the interface of mitochondria‐cell communication. OMM protein kinases phosphorylate diverse mitochondrial substrates that have discrete effects on organelle dynamics, protein import, respiratory complex activity, antioxidant capacity, and apoptosis. OMM phosphorylation events can be tempered through the actions of local protein phosphatases, such as mitogen‐activated protein kinase phosphatase‐1 (MKP‐1) and protein phosphatase 2A (PP2A), to regulate the extent and duration of signaling. The central mediators of OMM signal transduction are the scaffold proteins because the relative abundance of these accessory proteins determines the magnitude and duration of a signaling event on the mitochondrial surface, which dictates the biological outcome of a local signal transduction pathway. The concentrations of scaffold proteins, such as A‐kinase anchoring proteins (AKAPs) and Sab (or SH3 binding protein 5—SH3BP5), have been shown to influence neuronal survival and vulnerability, respectively, in models of Parkinson's disease (PD), highlighting the importance of OMM signaling to health and disease. Despite recent progress, much remains to be discovered concerning the mechanisms of OMM signaling. Nonetheless, enhancing beneficial OMM signaling events and inhibiting detrimental protein‐protein interactions on the mitochondrial surface may represent highly selective approaches to restore mitochondrial health and homeostasis and mitigate organelle dysfunction in conditions such as PD.

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“…NPC1/Stard3 mediates contacts between LE/Ly and endoplasmic reticulum (ER), which mediate cholesterol transfer between these organelles ( 49 , 50 ). ER contacts with mitochondria facilitate their fusion, which is now recognized as a prime site of StAR activity ( 51 ). This rapid response to dual CRISPR Cas9 editing of StAR closely matched the cytoplasmic large CE accumulations in the adrenals, testes, and ovaries of StAR −/− mice, as well as in humans, who carry the loss of function StAR mutations ( 40 ).…”

Section: Discussionmentioning

confidence: 99%

Monitoring of Dual CRISPR/Cas9-Mediated Steroidogenic Acute Regulatory Protein Gene Deletion and Cholesterol Accumulation Using High-Resolution Fluorescence In Situ Hybridization in a Single Cell

Lee

Jefcoate

2017

Front. Endocrinol.

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Recent advances in fluorescence microscopy, coupled with CRISPR/Cas9 gene editing technology, provide opportunities for understanding gene regulation at the single-cell level. The application of direct imaging shown here provides an in situ side-by-side comparison of CRISPR/Cas9-edited cells and adjacent unedited cells. We apply this methodology to the steroidogenic acute regulatory protein (StAR) gene in Y-1 adrenal cells and MA-10 testis cells. StAR is a gatekeeper protein that controls the access of cholesterol from the cytoplasm to the inner mitochondria. The loss of this mitochondrial cholesterol transfer mediator rapidly increases lipid droplets in cells, as seen in StAR−/− mice. Here, we describe a dual CRISPR/Cas9 strategy marked by GFP/mCherry expression that deletes StAR activity within 12 h. We used single-molecule fluorescence in situ hybridization (sm-FISH) imaging to directly monitor the time course of gene editing in single cells. We achieved StAR gene deletion at high efficiency dual gRNA targeting to the proximal promoter and exon 2. Seventy percent of transfected cells showed a slow DNA deletion as measured by PCR, and loss of Br-cAMP stimulated transcription. This DNA deletion was seen by sm-FISH in both loci of individual cells relative to non-target Cyp11a1 and StAR exon 7. sm-FISH also distinguishes two effects on stimulated StAR expression without this deletion. Br-cAMP stimulation of primary and spliced StAR RNA at the gene loci were removed within 4 h in this dual CRISPR/Cas9 strategy before any effect on cytoplasmic mRNA and protein occurred. StAR mRNA disappeared between 12 and 24 h in parallel with this deletion, while cholesterol ester droplets increased fourfold. These alternative changes match distinct StAR expression processes. This dual gRNA and sm-FISH approach to CRISPR/Cas9 editing facilitates rapid testing of editing strategies and immediate assessment of single-cell adaptation responses without the perturbation of clonal expansion procedures.

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The role of mitochondrial fusion and StAR phosphorylation in the regulation of StAR activity and steroidogenesis

Cited by 51 publications

References 98 publications

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure

Phosphoregulation on mitochondria: Integration of cell and organelle responses

Monitoring of Dual CRISPR/Cas9-Mediated Steroidogenic Acute Regulatory Protein Gene Deletion and Cholesterol Accumulation Using High-Resolution Fluorescence In Situ Hybridization in a Single Cell

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