Mitochondrial metabolic regulation by GRP78

Prasad, Manoj; Pawlak, Kevin J.; Burak, William E.; Perry, Elizabeth E.; Marshall, Brendan; Whittal, Randy M.; Bose, Himangshu S.

doi:10.1126/sciadv.1602038

Cited by 69 publications

(57 citation statements)

References 36 publications

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“…Recently, in steroid-producing cells, the cholesterol transport steroidogenic acute regulatory (StAR) protein, which shuttles cholesterol from the OMM to the IMM was found to be localized to the MAMs where it interacts with the voltage-dependent anion channel 2, enabling StAR to enter in the mitochondrial matrix and regulate steroidogenesis ( 57 , 58 ). Interestingly, the generation of the intermediate StAR folding state required for the delivery of cholesterol to the mitochondria occurs at the MAMs and necessitates the presence of the ER-chaperone glucose-regulated protein 78 (GRP78) ( 59 ). This mechanism, operating at the ER–mitochondria appositions, therefore couples crucial sensors of unfolded proteins and ER proteostasis (see below), like the chaperone GRP78, to critical mitochondrial functions of steroid-producing cells ( 59 ).…”

Section: Fundamental Structural and Functional Roles Of The Mamsmentioning

confidence: 99%

“…Interestingly, the generation of the intermediate StAR folding state required for the delivery of cholesterol to the mitochondria occurs at the MAMs and necessitates the presence of the ER-chaperone glucose-regulated protein 78 (GRP78) ( 59 ). This mechanism, operating at the ER–mitochondria appositions, therefore couples crucial sensors of unfolded proteins and ER proteostasis (see below), like the chaperone GRP78, to critical mitochondrial functions of steroid-producing cells ( 59 ).…”

Section: Fundamental Structural and Functional Roles Of The Mamsmentioning

confidence: 99%

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Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

2017

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The tight cross talk between two essential organelles of the cell, the endoplasmic reticulum (ER) and mitochondria, is spatially and functionally regulated by specific microdomains known as the mitochondria-associated membranes (MAMs). MAMs are hot spots of Ca 2+ transfer between the ER and mitochondria, and emerging data indicate their vital role in the regulation of fundamental physiological processes, chief among them mitochondria bioenergetics, proteostasis, cell death, and autophagy. Moreover, and perhaps not surprisingly, it has become clear that signaling events regulated at the ER-mitochondria intersection regulate key processes in oncogenesis and in the response of cancer cells to therapeutics. ER-mitochondria appositions have been shown to dynamically recruit oncogenes and tumor suppressors, modulating their activity and protein complex formation, adapt the bioenergetic demand of cancer cells and to regulate cell death pathways and redox signaling in cancer cells. In this review, we discuss some emerging players of the ER-mitochondria contact sites in mammalian cells, the key processes they regulate and recent evidence highlighting the role of MAMs in shaping cell-autonomous and non-autonomous signals that regulate cancer growth.Keywords: endoplasmic reticulum, mitochondria, mitochondria-associated membranes, Ca 2+ signaling, eR stress, autophagy, inflammasome, cancer cell Abbreviations: AA, arachidonoyl; ATF4, activating transcription factor 4; ATG, autophagy-related gene; Bcl-2, B-cell lymphoma 2; Bcl-XL, B-cell lymphoma-extra large; BECN1, Beclin-1; Ca 2 + , calcium; Cav-1, caveolin-1; CL, cardiolipin; CNX, calnexin; cyt c, cytochrome c; Drp1, dynamin-related protein 1; ER, endoplasmic reticulum; Grp78, glucose-regulated protein 78; HK2, hexokinase 2; IL-1β, interleukin 1β; IL-18, interleukin 18; IP3, inositol trisphosphate; IP3R, inositol 1, 4, 5-trisphosphate receptor; IP3R3, inositol 1, 4, 5-trisphosphate receptor 3; IRE1, inositol requiring enzyme 1; MAMs, mitochondria-associated membranes; MAVS, mitochondrial antiviral-signaling protein; MCU, mitochondrial calcium uniporter; MFN2, mitofusin 2; mTORC2, mammalian target of rapamycin 2; NLRP3, NOD-like receptor family 3; OMM, outer mitochondrial membrane; ORP5, oxysterol-binding protein (OSBP)-related protein (ORP) 5; ORP8, oxysterol-binding protein (OSBP)-related protein (ORP) 8; PA, phosphatidic acid; PACS-2, phosphofurin acidic cluster sorting protein 2; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PERK, double stranded RNA-activated protein kinase (PKR)-like ER kinase; PI, phosphatidylinositol; PM, plasma membrane; PML, promyelocytic leukemia; PP2A, protein phosphatase 2A; PS, phosphatidylserine; PTEN, phosphatase and tensin homolog deleted on chromosome 10; PTPIP51, protein tyrosine phosphatase-interacting protein 51; ROS, reactive oxygen species; SERCA, sarco/endoplasmic reticulum Ca 2+ ATPase; SERCA2b, sarco/endoplasmic reticulum Ca 2 + ATPase isoform 2b; Sigma1 receptor, S1R; StAR, cholesterol transport steroidogenic acute regula...

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Section: Fundamental Structural and Functional Roles Of The Mamsmentioning

confidence: 99%

Section: Fundamental Structural and Functional Roles Of The Mamsmentioning

confidence: 99%

Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

2017

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“…Money kidney (COS-1) cells were cultured in Dulbecco's modified Eagle's medium with high glucose supplemented with 10% FBS and penicillin-streptomycin. For transfection experiments, Lipofectamine or Oligofectamine (Thermo Fisher) was used as previously described (19,42,43).…”

Section: Methodsmentioning

confidence: 99%

“…In brief, mitochondrial membrane responsiveness was determined using an ATP assay system bioluminescence detection kit (ENLITEN; Promega) with a luminometer (Veritas microplate luminometer; Turner Biosystems, Sunnyvale, CA) by following the manufacturer's protocol. ATP production was inhibited by incubation of MA-10 cells with various concentrations of carbonyl cyanide m-chlorophenyl hydrazone (mCCP) for 1 h by following our previously described procedure (42). Tim50 knockdown experiments were performed with three different siRNAs, where siRNA1 (5=GGACAU CUCCUGUCUGAAUtt3= and 5=AUUCAGACAGGAGAUGUCCtt3=), siRNA2 (5=GCAUCGUCUAUAUUUUUGG tt3= and 5=CCAAAAAUAUAGACGAUGCtg3=), and siRNA3 (5=GGGACAUCAUGAAGGACtt3= and 5=GUCCUU CACAUGAUGUCCCtc3=) were independently transfected to cells with Oligofectamine (Thermo Fisher) (43).…”

Section: Methodsmentioning

confidence: 99%

Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis

Bose

Gebrail

Marshall³

et al. 2019

Molecular and Cellular Biology

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Adrenal and gonadal mitochondrial metabolic activity requires electrons from cofactors, cholesterol, and a substrate for rapid steroid synthesis, an essential requirement for mammalian survival. Substrate activity depends on its environment, which is regulated by chaperones and mitochondrial translocases. Cytochrome P450 side-chain cleavage enzyme (SCC or CYP11A1) catalyzes cholesterol to pregnenolone conversion, although its mechanism of action is not well understood. We find that SCC is directly imported into the mitochondrial matrix, where its N-terminal sequence is cleaved sequentially, after which it becomes activated following the second cleavage, which is dependent on the folding of the protein. Following integration of the SCC C terminus into the TIM23 complex, amino acids 141 to 146 interact with the intermembrane-exposed Tim50 protein, forming a large complex. The absence of Tim50 or its mutation reduced enzymatic activity. For the first time, we report that a protein activated at the matrix remains mostly unfolded and is transported back to the IMS to integrate with the TIM23 translocase complex and align with the Tim50 protein. Amino acid changes that suppress the association of Tim50 with SCC ablate metabolic activity. Thus, the TIM23 complex is the central regulator of metabolism guided by Tim50.

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“…appropriate folding of STAR is lost, resulting in ablation of STAR expression and complete shutdown of mitochondrial steroidogenesis (8).…”

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confidence: 99%

Mutation Spectrum of STAR and the Founder Effect of p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia

Kang

Kim

et al. 2017

Mol Med

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Congenital lipoid adrenal hyperplasia (CLAH) is the most severe form of congenital adrenal hyperplasia, caused by defects in the steroidogenic acute regulatory protein (STAR). The STAR p.Q258* mutation is the most common mutation in China, Japan and Korea, suggesting a founder effect. This study aimed to investigate the phenotypic and mutation spectrum of STAR defects and identify the founder effect of the p.Q258* mutation in Korean patients with CLAH. For 45 patients from 42 independent pedigrees, haplotype analysis was performed in 10 unrelated trio families, including patients with the p.Q258* mutation whose DNA samples were available, using 1,972 single nucleotide polymorphism (SNP) and six short tandem repeat markers. An Illumina Infinium® Human Omni2.5-8 v1.3 performed the SNP genotyping. Among 84 alleles from 42 unrelated families, mutation p.Q258* was found in 74 alleles (88.1%) from 41 families. A shared haplotype was identified in 17 of 20 alleles from 10 patients (size, 198 kb). The age of the founder mutation was estimated as 4,875 years (95% credible set: 3,575-7,925 years), assuming an intergenerational time interval of 25 years. The STAR p.Q258* mutation is the most common in Korean patients with CLAH, suggesting a founder effect. The age of the mutation corresponds with the time when the Korean people settled in the Korean peninsula. The high prevalence of p.Q258* in Japan and China also suggests a founder effect in Asian countries.

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Mitochondrial metabolic regulation by GRP78

Abstract: ER chaperone GRP78 is the central regulator of adrenals and gonadal steroid synthesis for mammalian survival.

Cited by 69 publications

References 36 publications

Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

Mitochondria-Associated Membranes As Networking Platforms and Regulators of Cancer Cell Fate

Inner Mitochondrial Translocase Tim50 Is Central in Adrenal and Testicular Steroid Synthesis

Mutation Spectrum of STAR and the Founder Effect of p.Q258* in Korean Patients with Congenital Lipoid Adrenal Hyperplasia

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