Mitochondria-associated Endoplasmic Reticulum Membrane (MAM) Regulates Steroidogenic Activity via Steroidogenic Acute Regulatory Protein (StAR)-Voltage-dependent Anion Channel 2 (VDAC2) Interaction

Prasad, Manoj; Kaur, Jasmeet; Pawlak, Kevin J.; Bose, Mahuya; Whittal, Randy M.; Bose, Himangshu S.

doi:10.1074/jbc.m114.605808

Cited by 130 publications

(130 citation statements)

References 51 publications

(67 reference statements)

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“…These results suggest that the interaction between Tom22 and 3␤HSD2 is strong but transient and not mediated by covalent linkages or embedded in each other through the vesicles. The density distribution of the outer mitochondrial resident VDAC2 or Tom40 was identical to the distribution pattern that we observed earlier (49).…”

Section: ␤Hsd2 Amino and Carboxyl Termini Are Strongly Conservedsupporting

confidence: 87%

“…Mass spectrometric analysis of this particular band identified both Tom22 (KLQMEQQQQLQQA, LQ MEQQQQL, and GATFDLSL) and 3␤HSD2 (TVEWVGSLVDR, DPQLVPILIDAAR, and TSEWIGTLVEQHR) proteins. We also cross-linked MA-10 cells in vivo with various concentrations of BS 3 to examine the interaction between 3␤HSD2 and Tom22 in a similar fashion as performed previously (49). Interaction between 3␤HSD2 and Tom22 was initiated with 2 mM BS 3 , and band intensity increased with increasing cross-linker concentrations, decreasing with Ն5 mM cross-linker (Fig.…”

Section: ␤Hsd2 Amino and Carboxyl Termini Are Strongly Conservedmentioning

confidence: 81%

“…Tom22 interacts with the polar surface of the amphipathic presequences through its negatively charged acid-rich region (15,16,18,23). However, Tom22 does not participate in the mitochondrial translocation of steroidogenic proteins, including cytochrome P450scc, AS, and StAR (49). These results suggest that proteins can reach the mitochondria without the direct assistance of Tom22.…”

Section: Discussionmentioning

confidence: 93%

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An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

Rajapaksha

Kaur

Prasad

et al. 2016

Molecular and Cellular Biology

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dAfter cholesterol is transported into the mitochondria of steroidogenic tissues, the first steroid, pregnenolone, is synthesized in adrenal and gonadal tissues to initiate steroid synthesis by catalyzing the conversion of pregnenolone to progesterone, which is mediated by the inner mitochondrial enzyme 3␤-hydroxysteroid dehydrogenase 2 (3␤HSD2). We report that the mitochondrial translocase Tom22 is essential for metabolic conversion, as its knockdown by small interfering RNA (siRNA) completely ablated progesterone conversion in both steroidogenic mouse Leydig MA-10 and human adrenal NCI cells. Tom22 forms a 500-kDa complex with mitochondrial proteins associated with 3␤HSD2. Although the absence of Tom22 did not inhibit mitochondrial import of cytochrome P450scc (cytochrome P450 side chain cleavage enzyme) and aldosterone synthase, it did inhibit 3␤HSD2 expression. Electron microscopy showed that Tom22 is localized at the outer mitochondrial membrane (OMM), while 3␤HSD2 is localized at the inner mitochondrial space (IMS), where it interacts through a specific region with Tom22 with its C-terminal amino acids and a small amino acid segment of Tom22 exposed to the IMS. Therefore, Tom22 is a critical regulator of steroidogenesis, and thus, it is essential for mammalian survival. Mitochondrial function is not limited to oxidative phosphorylation, as mitochondria are the site of steroid synthesis in specialized cells. Most mitochondrial proteins are expressed by nuclear genes with the mitochondrial targeting information in the mature protein. For example, some inner mitochondrial matrix (IMM) proteins have an internal, positively charged "presequence"-like signal, often preceded by a hydrophobic sequence (1), which leads to the arrest of translocation in the IMM and the subsequent lateral release of the protein into the lipid phase of the membrane (2). Import and subsequent intramitochondrial sorting of mitochondrial proteins are mediated by the mitochondrial membrane protein translocases. The translocase complexes in the outer mitochondrial membrane (OMM) are not tightly linked with those of the IMM; yet, they dynamically cooperate to achieve protein delivery to each mitochondrial subcompartment. To understand the mechanism of protein transport by the mitochondrial import/sorting system, it is essential to monitor and analyze the dynamic interactions among the constituents of the system. Steroidogenic cells do not store steroid hormone; therefore, an immediate steroidogenic response requires rapid synthesis of new steroid. Cholesterol mitochondrial transport initiates inner mitochondrial metabolic activity in steroidogenic cells within adrenal and gonadal tissues as well as the brain. Conversion of the first steroid, pregnenolone, to progesterone is catalyzed by 3␤-hydroxysteroid dehydrogenase 2 (3␤HSD2). Due to its central role in steroidogenesis, changes in 3␤HSD2 activity can have a wide range of effects, including hypertension, salt wasting crisis, and impaired sexual development (3-7). We have also identified p...

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Section: ␤Hsd2 Amino and Carboxyl Termini Are Strongly Conservedsupporting

confidence: 87%

Section: ␤Hsd2 Amino and Carboxyl Termini Are Strongly Conservedmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 93%

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An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

Rajapaksha

Kaur

Prasad

et al. 2016

Molecular and Cellular Biology

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“…Recent evidence suggests that V2 is involved in Ca 2+ transport by cardiac mitochondria (6)(7)(8), and specifically interacts with several endogenous cytoplasmic and mitochondria-associated proteins, including steroidogenic acute regulatory protein (StAR) (9), glycogen synthase kinase 3 beta (GSK3β) (10), O-GlcNAc transferase (11), ryanodine receptor 2 (8), tubulin (12), viral protein 5, (13,14), and drugs [erastin (15) and esfevin (7)]. These interactions facilitate mitochondrial targeting, transport, and signaling processes, and, interestingly, they seem to have striking effects on cell survival.…”

mentioning

confidence: 99%

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Naghdi

Várnai

Hajnóczky

2015

Proc. Natl. Acad. Sci. U.S.A.

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Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2 −/− (V2 −/− ) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2 −/− fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-offunction studies, V2 (123-179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open "pocket" on the cytoplasmic surface that could facilitate Bak recruitment.

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“…Our observation that LDs in MLTC-1 are rearranged after LH stimulation suggests that the LD-ER interaction provides a type of platform for steroidogenesis in which all of the enzymes and cholesterol are gathered at the same sites. One interesting possibility that was raised very recently is that StAR interacts with voltage-dependent anion channel 2 (VDAC2) at sites of mitochondria-associated ER membrane (MAM) to form a center for steroidogenesis [35].…”

Section: Morphological Change In the Ld Structure Induced By Hormonalmentioning

confidence: 99%

Characterization of lipid droplets in steroidogenic MLTC-1 Leydig cells: Protein profiles and the morphological change induced by hormone stimulation

Yamaguchi

Fujikawa

Nimura

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Mitochondria-associated Endoplasmic Reticulum Membrane (MAM) Regulates Steroidogenic Activity via Steroidogenic Acute Regulatory Protein (StAR)-Voltage-dependent Anion Channel 2 (VDAC2) Interaction

Cited by 130 publications

References 51 publications

An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

An Outer Mitochondrial Translocase, Tom22, Is Crucial for Inner Mitochondrial Steroidogenic Regulation in Adrenal and Gonadal Tissues

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

Characterization of lipid droplets in steroidogenic MLTC-1 Leydig cells: Protein profiles and the morphological change induced by hormone stimulation

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