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Transcriptional Regulatory Circuits Controlling Mitochondrial Biogenesis and Function

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Transcriptional Regulatory Circuits Controlling Mitochondrial Biogenesis and Function Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Transcriptional regulatory circuits controlling mitochondrial biogenesis and function Daniel P. Kelly1,3 and Richard C. Scarpulla2 1Center for Cardiovascular Research, Departments of Medicine, Molecular Biology & Pharmacology, and Pediatrics, Washington University School of Medicine, St.Louis, Missouri 63119, USA ; 2Department of Cell and Molecular Biology, Northwestern Medical School, Chicago, Illinois 60611, USA We are witnessing a period of renewed interest in the The limited coding capacity of mtDNA necessitates biology of the mitochondrion.The mitochondrion serves that nuclear genes make a major contribution to mito- a critical function in the maintenance of cellular energy chondrial metabolic systems and molecular architecture stores, thermogenesis, and apoptosis.Moreover, alter- (Garesse and Vallejo 2001).One major class of nuclear ations in mitochondrial function contribute to several genes contributes catalytic and auxiliary proteins to the inherited and acquired human diseases and the aging mitochondrial enzyme systems.For example, the major- process.This review summarizes our understanding of ity of the 100 or so subunits of the respiratory apparatus the transcriptional regulatory mechanisms involved in are nucleus-encoded.In addition, nucleus-encoded meta- the biogenesis and energy metabolic function of mito- bolic enzymes necessary for the oxidation of pyruvate, chondria in higher organisms. fatty acids (␤-oxidation cycle), and acetyl-CoA (tricar- boxylic acid cycle), the biosynthesis of certain amino acids, and the manufacture of heme, among others, The mitochondrial genome are localized to the mitochondrion.A second class of nuclear genes encodes protein import and assembly fac- A defining feature of eukaryotic cells is that they contain tors.A third class contributes key proteins that are re- nuclear and mitochondrial genomes sequestered into quired for the replication and expression of the mito- distinct subcellular compartments.The mitochondrial chondrial genome including nucleic acid polymerases, genetic system is comprised of a circular DNA genome RNA processing enzymes, transcription and replication (mtDNA, ∼16.5 kb in vertebrates; Fig. 1), the enzymes factors as well as tRNA-synthetases, translation factors, required for its transcription and replication, and the pro- and ribosomal subunits.Thus, the program regulating tein synthetic machinery necessary for the translation of mitochondrial biogenesis involves the coordinate ac- 13 mitochondrial mRNAs (for review, see Garesse and tions of nuclear and mitochondrial genes. Vallejo 2001).These mRNAs, which account for the en- tire protein-coding capacity of mtDNA, encode essential subunits of respiratory complexes I, III, IV, and V.The Regulatory proteins involved in mitochondrial extrusion of protons through complexes I, III, and IV is gene transcription coupled to the sequential transfer of electrons to a series of carriers of increasing redox potential resulting in an In yeast, mtDNA transcription is initiated at ∼20 tran- electrochemical proton gradient across the inner mem- scriptional units throughout the genome (for review, see brane.Complex V, comprised of an ATPase coupled to Poyton and McEwen 1996).In vertebrates, transcription an inner membrane proton channel, can dissipate the is initiated bidirectionally at two promoters, PH and PL proton gradient in the synthesis of ATP or can couple for heavy (H) and light strands (L), respectively, within proton pumping to ATP hydrolysis to maintain the gra- the D-loop regulatory region (Shadel and Clayton 1997; dient.mtDNA also encodes for two ribosomal and 22 Clayton 2000).The D-loop is the longest noncoding re- transfer RNAs, required for translation by mitoribo- gion in vertebrate mtDNA and contains, in addition to somes within the matrix. PH and PL, the H-strand replication origin (OH; Fig.1).In the “strand asymmetric model” of mtDNA replication, the RNA transcript initiated at PL is cleaved in the vi- cinity of three evolutionarily conserved sequence blocks 3Corresponding author. (CSB I, II, and III), and H-strand replication is initiated at E-MAIL [email protected]; FAX (314) 362-0186. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ the sites of these cleavages (Bogenhagen and Clayton gad.1177604. 2003).Thus, transcription is coupled to DNA replication GENES & DEVELOPMENT 18:357–368 © 2004 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/04; www.genesdev.org 357 Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Kelly and Scarpulla Figure 1. Human mitochondrial DNA (mtDNA).The genomic organization and structural features of human mtDNA are depicted in a circular genomic map.The D-loop regulatory region is expanded and shown above. Protein coding and rRNA genes are interspersed with 22 tRNA genes (denoted by the single-letter amino acid code).The D-loop regulatory region contains the L- and H-strand promoters (PL and PH, respectively) along with the origin of H-strand replication (OH).mtDNA trans- cription complexes containing mitochondrial RNA poly- merase, Tfam, and TFB are depicted in the expanded D-loop along with the conserved sequence blocks (CSB I, II, and III).The origin of L-strand replication (O L)is displaced by approximately two-thirds of the genome within a cluster of five tRNA genes.Protein-coding genes include cytochrome oxidase (COX) subunits 1, 2, and 3; NADH dehydrogenase (ND) subunits 1, 2, 3, 4, 4L, 5, and 6; ATP synthase (ATPS) subunits 6 and 8; and cytochrome b (Cytb). ND6 and the eight tRNA genes encoded on the L-strand are in bold type and under- lined; all other genes are encoded on the H-strand. and the sites of RNA cleavage are transition sites be- Several lines of evidence indicate that Tfam is required tween RNA and DNA synthesis.A decision must be for mtDNA replication and maintenance. Tfam knock- made to continue transcription through the CSBs or to out mice display embryonic lethality and depletion of truncate the nascent RNA to initiate DNA replication. mtDNA (Larsson et al.1998).In addition, Tfam levels After DNA synthesis begins, the nascent strand is often correlate well with increased mtDNA in ragged-red terminated downstream from a conserved element re- muscle fibers and decreased mtDNA levels in mtDNA- ferred to as a termination-associated sequence (TAS). depleted cells (Larsson et al.1994; Poulton et al.1994). This event accounts for the triple-stranded D-loop struc- ABF2, a related HMG-box yeast factor, is required for ture and may be important in controlling mtDNA levels mtDNA maintenance and respiratory competence (Diff- (Brown and Clayton 2002). ley and Stillman 1991).Expression of Tfam can comple- The mitochondrial H- and L-strand transcriptional ment an ABF2 deficiency in yeast, suggesting that the units differ from most nuclear genes in that they are two proteins are functionally homologous (Parisi et al. polygenic.In addition to the RNA primer for H-strand 1993).Interestingly, despite this functional complemen- replication, PL also directs the synthesis of a transcript tation, ABF2 lacks an activation domain present in Tfam that is processed to one mRNA and eight of the 22 tRNAs. and does not stimulate transcription (Dairaghi et al. The polygenic transcript directed by PH is processed to 1995). 14 tRNAs, 12 mRNAs, and the two rRNAs (for review, Significant progress has been made in the character- see Garesse and Vallejo 2001).Both promoters share a ization of the mtDNA transcription initiation machin- critical upstream enhancer that serves as the recognition ery.A vertebrate mitochondrial RNA polymerase and a site for mitochondrial transcription factor A or Tfam specificity factor that are required for mitochondrial-spe- (previously mtTF-1 and mtTFA), an HMG-box protein cific initiation were initially identified and characterized that stimulates transcription through specific binding to in Xenopus laevis (Antoshechkin and Bogenhagen 1995; upstream enhancers.Like other HMG proteins, Tfam Bogenhagen 1996).Although purification of the human can bend and unwind DNA, properties potentially linked polymerase has been elusive, a human cDNA that en- to its ability to stimulate transcription upon binding codes a protein with sequence similarity to yeast mito- DNA (Fisher et al.1992).In addition to specific promoter chondrial and phage polymerases has been identified in recognition, Tfam binds nonspecific DNA with high af- database screenings (Tiranti et al.1997).The encoded finity.This property along with its abundance in mito- protein localizes to mitochondria, suggesting that it is a chondria suggests that it plays a role in the stabilization bona fide mitochondrial polymerase.A human mito- and maintenance of the mitochondrial chromosome chondrial transcription factor B (h-mtTFB) cDNA has through its phased binding to nonpromoter sites (Parisi also been isolated, and the encoded protein has proper- et al.1993). ties consistent with it being a functional homolog of the 358 GENES & DEVELOPMENT Downloaded from genesdev.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Regulation of mitochondrial biogenesis yeast specificity factor, sc-mtTFB (McCulloch et al. taining clusters of hydrophobic amino acid residues 2002).The protein is localized to mitochondria and can (Chau et al.1992; Gugneja et al.1996).Both endogenous bind DNA and stimulate transcription from an L-strand and recombinant proteins bind as a homodimer to pal- promoter in vitro.Subsequently, two isoforms of h-mtTFB, indromic NRF-1 sites through guanine nucleotide con- termed TFB1 and 2, were identified (Falkenberg et al. tacts over a single turn of the DNA helix (Virbasius et al. 2002).TFB1 is identical to the initial h-mtTFB isolate. 1993a).Serine phosphorylation of the N-terminal do- Like the yeast factor, both TFBs share sequence similari- main of NRF-1 enhances both its DNA-binding (Gugneja ties with rRNA dimethyltransferases, although the simi- and Scarpulla 1997) and trans-activation functions (Her- larity between TFB2 and this class of enzymes is weaker zig et al.2000).
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