Mitochondrial endocrinology Mitochondria as key to hormones and metabolism
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. Yen, P.M., Ando, S., Feng, X., Liu, Y., Maruvada, P., Xia, X., 2006. Thyroid hormone action at the cellular, genomic and target gene levels. Mol. Cell. Endocrinol. 246 (1–2), 121–127 . F. Cioffi et al. / Molecular and Cellular Endocrinology 379 (2013) 51–61 61 Steroid hormone synthesis in mitochondria Walter L. Miller ⇑ Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-1346, USA Division of Endocrinology, University of California San Francisco, San Francisco, CA 94143-1346, USA a r t i c l e i n f o Article history: Available online 28 April 2013 Keywords: Cholesterol transport Cholesterol side chain cleavage Outer mitochondrial membrane Steroidogenesis Steroidogenic acute regulatory protein Vitamin D a b s t r a c t Mitochondria are essential sites for steroid hormone biosynthesis. Mitochondria in the steroidogenic cells of the adrenal, gonad, placenta and brain contain the cholesterol side-chain cleavage enzyme, P450scc, and its two electron-transfer partners, ferredoxin reductase and ferredoxin. This enzyme system converts cholesterol to pregnenolone and determines net steroidogenic capacity, so that it serves as the chronic regulator of steroidogenesis. Several other steroidogenic enzymes, including 3b-hydroxysteroid dehydro- genase, 11b-hydroxylase and aldosterone synthase also reside in mitochondria. Similarly, the mitochon- dria of renal tubular cells contain two key enzymes participating in the activation and degradation of vitamin D. The access of cholesterol to the mitochondria is regulated by the steroidogenic acute regula- tory protein, StAR, serving as the acute regulator of steroidogenesis. StAR action requires a complex multi-component molecular machine on the outer mitochondrial membrane (OMM). Components of this machine include the 18 kDa translocator protein (TSPO), the voltage-dependent anion chanel (VDAC-1), TSPO-associated protein 7 (PAP7, ACBD3), and protein kinase A regulatory subunit 1 a (PKAR1A). The pre- cise fashion in which these proteins interact and move cholesterol from the OMM to P450scc, and the means by which cholesterol is loaded into the OMM, remain unclear. Human deficiency diseases have been described for StAR and for all the mitochondrial steroidogenic enzymes, but not for the electron transfer proteins or for the components of the cholesterol import machine. Ó 2013 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Six classes of steroid hormones, all of which are indispensable for mammalian life, are made from cholesterol via complex biosyn- thetic pathways that are initiated by specialized, tissue-specific en- zymes found in mitochondria. These hormones include glucocorticoids (cortisol, corticosterone) and mineralocorticoids (aldosterone) produced in the adrenal cortex; estrogens (estradiol), progestins (progesterone) and androgens (testosterone, dihydro- testosterone) produced in the gonads; and calciferols (1,25-dihy- droxy vitamin D [1,25OH 2 D]) produced in the kidney. The biosynthesis of the steroid hormones ( Miller and Auchus, 2011 ) and of 1,25OH 2 D (a sterol) ( Feldman et al., 2013 ) from cholesterol have been reviewed recently. There are two specialized aspects to the mitochondria of these steroidogenic tissues – the specialized mechanisms by which cholesterol is delivered to the mitochondria and the specialized intra-mitochondrial enzymes that paricipate in the synthesis of hormonal steroids. 2. Delivery of cholesterol to mitochondria 2.1. Sources of cholesterol The intracellular transport and distribution of cholesterol prior to its delivery to the mitochondria has been reviewed recently ( Miller and Bose, 2011 ). Cholesterol may be produced de novo from acetate via a complex pathway primarily found in the endoplasmic 0303-7207/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mce.2013.04.014 Abbreviations: 1,25(OH) 2 D, 1,25 dihydroxy vitamin D (calcitriol); 3bHSD, 3b- hydroxysteroid dehydrogenase; ACAT, acyl transferase; ACTH, adrenocorticotropic hormone; ANT, adenine nucleotide transporter; ER, endoplasmic reticulum; CRAC, cholesterol recognition amino acid consensus domain; FAD, flavin adenine dinu- cleotide; HDL, high density lipoproteis; HSL, hormone-sensitive neutral lipase; HMGCoA, 3-hydroxy-3-methylglutaryl co-enzyme A; IMM, inner mitochondrial membrane; IMS, intramembranous space; Km, Michaelis constant; LAL, lysosomal acid lipase; LDL, low-density lipoproteins; LH, luteinizing hormone; MENTAL, MLN64 N-terminal; MENTHO, MLN64 N-terminal domain homologue; MLN64, metastatic lymph node clone 64; NADPH, nicotinamide adenine dinucleotide phosphate; NPC, Niemann Pick type C; OMM, outer mitochondrial membrane; PAP7, TSPO-associated protein 7 (ACBD3); PBR, peripheral benzodiazepine recep- tor; PCP, phosphate carrier protein; PKA, protein kinase A; PKAR1A, protein kinase A regulatory subunit 1 a ; PRAX1, TSPO-associated protein 1; PTH, parathyroid hormone; P450scc, mitochondrial cytochrome P450 specific for cholesterol side- chain cleavage; SF1, steroidogenic factor 1; SOAT, sterol O-acetyltransferase; SR-B1, scavenger receptor B1; StAR, steroidogenic acute regulatory protein; START, StAR- related lipid transfer domain; SREBPs, sterol regulatory element binding proteins; TSPO, 18 kDa translocator protein; VDAC1, voltage-dependent anion channel. ⇑ Address: Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143-1346, USA. E-mail address: wlmlab@ucsf.edu Molecular and Cellular Endocrinology 379 (2013) 62–73 Contents lists available at SciVerse ScienceDirect Molecular and Cellular Endocrinology j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e reticulum (ER) ( Porter and Herman, 2011 ), but most steroidogenic cholesterol is derived from circulating lipoproteins. High density lipoproteins (HDL) may be taken up via scavenger receptor B1 (SR-B1) and low-density lipoproteins (LDL) are taken up by recep- tor-mediated endocytosis via LDL receptors. LDL can suppress the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-meth- ylglutaryl co-enzyme A (HMGCoA) reductase. Rodents preferenti- aly use the HDL/SR-B1 pathway to obtain steroidogenic cholesterol, but the principal human source is receptor-mediated endocytosis of LDL. Nevertheless, patients with congenital abeta- lipoproteinemia have low LDL cholesterol but have normal basal cortisol concentrations, and only mildly impaired cortisol re- sponses to adrenocorticotropic hormone (ACTH) ( Illingworth et al., 1982 ), and those treated with high doses of statins have no impairment of cortisol secretion ( Dobs et al., 2000 ). Thus endoge- nously produced cholesterol is sufficient in most situations, and the HDL/SR-B1 system plays a relatively minor role in human ste- roidogenesis. The regulation of cholesterol uptake, intracellular transport, and utilization is coordinated by a family of basic he- lix-loop-helix transcription factors called the sterol regulatory ele- ment binding proteins (SREBPs). The cell biology of intracellular cholesterol trafficking is summarized in Fig. 1 .
After circulating LDL is internalized by receptor-mediated endo- cytosis, the resulting endocytic vesicles fuse with lysosomes, where the LDL proteins are degraded by proteolysis, liberating the cholesteryl esters, which are then hydrolyzed to ‘free’ choles- terol by lysosomal acid lipase (LAL). However, cholesterol is never truly free, as its solubility is only about 20 l mol per liter, so that the term ‘free cholesterol’ refers to cholesterol that is bound to pro- teins or membranes, but lacks a covalently linked group. Free cho- lesterol may be used by the cell or stored in lipid droplets following re-esterification by acyl-coenzyme-A-cholesterol-acyl-transferase (ACAT) also known as sterol-O-acetyltransferase (SOAT1). Simi- larly, HDL cholesteryl esters that enter the cell via SR-B1 are acted on by hormone-sensitive neutral lipase (HSL), following which the free cholesterol may also be used or re-esterified for storage. ACTH and luteinizing hormone (LH) respectively increase intracellular levels of cAMP in the adrenal and gonad, stimulating HSL and inhibiting ACAT, thus increasing the availability of free cholesterol for steroid hormone synthesis. ACTH, LH and other factors that in- crease cAMP stimulate the activity of HMGCoA reductase and the uptake of LDL cholesterol. When intracellular cholesterol concen- trations are high, the genes for the LDL receptor, HMGCoA reduc- tase and LAL are repressed while ACAT is induced, thereby decreasing cholesterol uptake, synthesis and de-esterification. Conversely, when intracellular cholesterol concentrations are low, this process is reversed. Mutations in the LIPA gene encoding LAL cause Wolman disease, characterized by visceral accumulation of cholesteryl esters and triglycerides, with secondary adrenal insufficiency; cholesterol es- ter storage disease is a milder, adult variant ( Lohse et al., 1999 ). Af- fected infants quickly develop hepatosplenomegaly, malabsorptive malnutrition and developmental delay; the diagnosis may be sug- gested by calcification that outlines the adrenal glands, and is established by finding deficient lysosomal acid lipase activity in leukocytes, fibroblasts or prenatal amniocytes. Bone marrow trans- plantation may ameliorate the disease, but the mechanism is un- clear. In contrast to LAL, no known human disease is associated with HSL deficiency. 2.3. Endosomal processing of cholesterol The entry and exit of cholesterol from lipid droplets involves the NPC proteins, so named because their mutation causes Nie- mann Pick type C (NPC) disease, which is characterized by endo- somal accumulation of LDL-cholesterol and glycosphingolipids. Patients are normal in infancy but develop ataxia, dementia, loss Fig. 1. Intracellular cholesterol trafficing. Human steroidogenic cells take up circulating low-density lipoproteins (LDLs) by receptor-mediated endocytosis, directing the cholesterol to endosomes; rodent cells utilize cholesterol from high-density lipoproteins (HDLs) via scavenger receptor B1 (SRB1). Cholesterol may also be synthesized from acetate in the ER. Cholesteryl esters are cleaved by lysosomal acid lipase (LAL); free cholesterol is then bound by NPC1, transferred to NPC2, and exported. The MLN64/ MENTHO system resides in the same endosomes as the NPC system, but its role in cholesterol trafficking remains uncertain. Cholesterol may be re-esterified by acyl-CoA: cholesterol transferase (ACAT) and stored in lipid droplets as cholesteryl esters. Free cholesterol may be produced by hormone-sensitive lipase (HSL). Cholesterol can reach the outer mitochondrial membrane (OMM) by non-vesicular means by utilizing START-domain proteins or other cholesterol transport proteins. Movement of cholesterol from the OMM to the inner mitochondrial membrane (IMM) requires a multi-protein complex on the OMM. In the adrenals and gonads, the steroidogenic acute regulatory protein, StAR, is responsible for the rapid movement of cholesterol from the OMM to the IMM, where it can be converted to pregnenolone by P450scc. ( ÓWL Miller). W.L. Miller / Molecular and Cellular Endocrinology 379 (2013) 62–73 63
of speech and spasticity at 2–4 years, and usually die during their second decade ( Vanier and Millat, 2003 ). Cholesterol and other lip- ids accumulate in Purkinje cells and other neurons, and there is ro- bust glial infiltration. The diagnosis is typically made by finding characteristic foamy Niemann-Pick cells and ‘sea-blue’ histiocytes in the bone marrow. The NPC1 or NPC2 proteins participate in endosomal/lysosomal cholesterol transport. NPC1 is a 1278 AA gly- coprotein containing 13 transmembrane domains that span the endo-lysosomal membrane ( Kwon et al., 2009 ), and NPC2 is a sol- uble 151 AA glycoprotein found in the lysosomal lumen ( Xu et al., 2007
). NPC2 binds cholesteryl esters with the cholesterol side- chain buried is in a hydrophobic pocket and the polar 3bOH group exposed, allowing LAL to cleave cholesteryl esters while they are bound to NPC2. The free cholesterol is then transferred to the N- terminal domain of NPC1 in the lysosomal lumen, which binds cholesterol the 3bOH group buried in the protein and the side chain partially exposed. Thus, the NPC2 and NPC1 proteins act to- gether to insert cholesterol into the lysosomal membrane with the hydrophobic side-chain going in first. Two proteins named MLN64 (metastatic lymph node clone 64) and MENTHO (MLN64 N-terminal domain homologue) may also participate in endosomal cholesterol trafficking. MLN64 is a cho- lesterol-binding protein that co-localizes with NPC1 in late endo- somes (
Zhang et al., 2002; Alpy and Tomasetto, 2006 ). The N- terminal ‘MENTAL’ domain (for MLN64 N-TerminAL) is structurally related to the late-endosomal protein, MENTHO ( Alpy et al., 2002 ), contains 4 transmembrane domains, and targets MLN64 to late endosomal membranes. The C-terminal domain of MLN64 is called the START (StAR-related lipid transfer) domain because it is similar to the lipid-biding domain of the steroidogenic acute regulatory protein (StAR) ( Alpy et al., 2001; Clark, 2012 ) (see Section 3). The MENTAL domains of MENTHO and MLN64 can interact to form homo- and heterodimers and to bind cholesterol, suggesting a role in endosomal cholesterol transport. MLN64 lacking the MENTAL domain (N-234 MLN64) has 50–60% of StAR-like activity to stimu- late mitochondrial uptake of cholesterol ( Bose et al., 2000 ). The START domain of MLN64 may interact with cytoplasmic HSP60 to stimulate steroidogenesis in placental mitochondria ( Olvera-
Sanchez et al., 2011 ). The function of MLN64 remains unclear: knockout of the START domain of MLN64 yielded viable, neurolog- ically intact, fertile mice with normal plasma and hepatic lipids ( Kishida et al., 2004 ), and no human disorders of MLN64 or MEN- THO have been described. Accumulation of cholesterol in NPC1- deficient cells increased MLN64-mediated cholesterol transport to mitochondria and accumulation of cholesterol in the outer mitochondiral membrane (OMM), suggesting that cholesterol transport from endosomes to mitochondria may involve MLN64 ( Charman et al., 2010 ). 2.4. Non-vesicular intracytoplasmic cholesterol transport Intracellular cholesterol transport may may be ‘vesicular’ (med- iated by membrane fusion) or ‘non-vesicular’ (bound to proteins). Because membranes participating in vesicular transport are fluid, the lipid compositions of the mitochondrial membranes may vary. Protein-protein interactions between lipid droplets, mitochondria, and other organelles may facilitate vesicular cholesterol transport. Both vesicular and non-vesicular cholesterol transport occur in ste- roidogenic cells, but non-vesicular transport involving high-affin- ity cholesterol-binding START-domain proteins appears to be the principal means of cholesterol transport from lipid droplets to mitochondria ( Miller and Bose, 2011 ). START-domain proteins are found in fungi, plants and animals; the mammalian START-do- main proteins are termed StarD1-15 ( Clark, 2012 ). The START pro- teins most closely related to StAR (StarD4, D5 and D6), bind cholesterol and are induced by SREBP. StarD4, D5, and D6 lack N- terminal signal sequences, suggesting they are cytosolic proteins. StarD1 (StAR), StarD3 (MLN64), StarD4 and StarD5 bind cholesterol with high affinity and specificity, facilitate cholesterol transport through an aqueous environment, and appear to play important roles in cellular cholesterol homeostasis ( Rodriguez-Agudo et al., Download 2.44 Mb. Do'stlaringiz bilan baham: 
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