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BBA - Gene Regulatory Mechanisms (v.1819, #9-10)
Mitochondrial DNA nucleoid structure by Daniel F. Bogenhagen (pp. 914-920).
Eukaryotic cells are characterized by their content of intracellular membrane-bound organelles, including mitochondria as well as nuclei. These two DNA-containing compartments employ two distinct strategies for storage and readout of genetic information. The diploid nuclei of human cells contain about 6billion base pairs encoding about 25,000 protein-encoding genes, averaging 120kB/gene, packaged in chromatin arranged as a regular nucleosomal array. In contrast, human cells contain hundreds to thousands of copies of a ca.16kB mtDNA genome tightly packed with 13 protein-coding genes along with rRNA and tRNA genes required for their expression. The mtDNAs are dispersed throughout the mitochondrial network as histone-free nucleoids containing single copies or small clusters of genomes. This review will summarize recent advances in understanding the microscopic structure and molecular composition of mtDNA nucleoids in higher eukaryotes. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► MtDNA nucleoids are packaged principally by the HMG box architectural transcription factor TFAM. ► The reported numbers of mtDNA molecules per nucleoid and nucleoids per cell varies widely. ► Sets of nucleoid associated proteins may shed light on aspects of mitochondrial biogenesis. ► Superresolution imaging provides important advances in understanding nucleoid structure.
Keywords: Mitochondria; mtDNA; Nucleoid
Mitochondrial transcription factor A regulates mitochondrial transcription initiation, DNA packaging, and genome copy number by Christopher T. Campbell; Jill E. Kolesar; Brett A. Kaufman (pp. 921-929).
Mitochondrial transcription factor A (mtTFA, mtTF1, TFAM) is an essential protein that binds mitochondrial DNA (mtDNA) with and without sequence specificity to regulate both mitochondrial transcription initiation and mtDNA copy number. The abundance of mtDNA generally reflects TFAM protein levels; however, the precise mechanism(s) by which this occurs remains a matter of debate. Data suggest that the usage of mitochondrial promoters is regulated by TFAM dosage, allowing TFAM to affect both gene expression and RNA priming for first strand mtDNA replication. Additionally, TFAM has a non-specific DNA binding activity that is both cooperative and high affinity. TFAM can compact plasmid DNA in vitro, suggesting a structural role for the non-specific DNA binding activity in genome packaging. This review summarizes TFAM-mtDNA interactions and describes an emerging view of TFAM as a multipurpose coordinator of mtDNA transactions, with direct consequences for the maintenance of gene expression and genome copy number. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► We review TFAM–DNA interactions, including specificity, affinity, bending, and cooperativity. ► We review proposed mechanisms of TFAM regulation of mtDNA copy number. ► We propose a model in which TFAM dimerization, DNA looping, and cooperativity impact mtDNA packaging and promoter activity.
Keywords: mtDNA; TFAM; Nucleoid; Mitochondrial gene expression; Replication; Mitochondrial biogenesis
Mechanism of transcription initiation by the yeast mitochondrial RNA polymerase by Aishwarya P. Deshpande; Smita S. Patel (pp. 930-938).
Mitochondria are the major supplier of cellular energy in the form of ATP. Defects in normal ATP production due to dysfunctions in mitochondrial gene expression are responsible for many mitochondrial and aging related disorders. Mitochondria carry their own DNA genome which is transcribed by relatively simple transcriptional machinery consisting of the mitochondrial RNAP (mtRNAP) and one or more transcription factors. The mtRNAPs are remarkably similar in sequence and structure to single-subunit bacteriophage T7 RNAP but they require accessory transcription factors for promoter-specific initiation. Comparison of the mechanisms of T7 RNAP and mtRNAP provides a framework to better understand how mtRNAP and the transcription factors work together to facilitate promoter selection, DNA melting, initiating nucleotide binding, and promoter clearance. This review focuses primarily on the mechanistic characterization of transcription initiation by the yeast Saccharomyces cerevisiae mtRNAP (Rpo41) and its transcription factor (Mtf1) drawing insights from the homologous T7 and the human mitochondrial transcription systems. We discuss regulatory mechanisms of mitochondrial transcription and the idea that the mtRNAP acts as the in vivo ATP “sensor” to regulate gene expression. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Mitochondrial (mt) RNA polymerases (RNAP) serve as an intriguing link between single and multi-subunit RNAPs. ► Although structurally similar to T7 RNAP, the mt RNAPs depend on accessory transcription factors. ► Both components bind the promoter and work cooperatively to catalyze promoter-specific initiation. ► Induced-fit mechanism involving DNA bending is employed to differentiate between promoter and non-promoters.
Keywords: Abbreviations; mtRNAP; mitochondrial RNAP; Ymt; yeast mitochondrial; Mtf1; mitochondrial transcription factor 1; nt; nucleotides; aa; amino acids; SAM; S-adenosyl-; l; -methionine; K; d; equilibrium dissociation constant; FRET; fluorescence resonance energy transfer; 2-AP; 2-aminopurine; K; m; Michaelis–Menten constantMitochondrial DNA transcription; Mitochondrial RNA polymerase; Rpo41; Mtf1
Hitting the brakes: Termination of mitochondrial transcription by Kip E. Guja; Miguel Garcia-Diaz (pp. 939-947).
Deficiencies in mitochondrial protein production are associated with human disease and aging. Given the central role of transcription in gene expression, recent years have seen a renewed interest in understanding the molecular mechanisms controlling this process. In this review, we have focused on the mostly uncharacterized process of transcriptional termination. We review how several recent breakthroughs have provided insight into our understanding of the termination mechanism, the protein factors that mediate termination, and the functional relevance of different termination events. Furthermore, the identification of termination defects resulting from a number of mtDNA mutations has led to the suggestion that this could be a common mechanism influencing pathogenesis in a number of mitochondrial diseases, highlighting the importance of understanding the processes that regulate transcription in human mitochondria. We discuss how these recent findings set the stage for future studies on this important regulatory mechanism. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Termination of transcription in mitochondria is not well characterized. ► Human MTERF1 mediates termination at a major site in tRNALeu. ► MTERF1 utilizes a unique binding mechanism to promote termination. ► There are connections between transcription termination and mtDNA replication. ► Other MTERF family members have been implicated in termination and replication.
Keywords: Mitochondrial transcription termination; MTERF; Mitochondria; Gene expression
Human mitochondrial RNA polymerase: Structure–function, mechanism and inhibition by Jamie J. Arnold; Eric D. Smidansky; Ibrahim M. Moustafa; Craig E. Cameron (pp. 948-960).
Transcription of the human mitochondrial genome is required for the expression of 13 subunits of the respiratory chain complexes involved in oxidative phosphorylation, which is responsible for meeting the cells' energy demands in the form of ATP. Also transcribed are the two rRNAs and 22 tRNAs required for mitochondrial translation. This process is accomplished, with the help of several accessory proteins, by the human mitochondrial RNA polymerase (POLRMT, also known as h-mtRNAP), a nuclear-encoded single-subunit DNA-dependent RNA polymerase (DdRp or RNAP) that is distantly related to the bacteriophage T7 class of single-subunit RNAPs. In addition to its role in transcription, POLRMT serves as the primase for mitochondrial DNA replication. Therefore, this enzyme is of fundamental importance for both expression and replication of the human mitochondrial genome. Over the past several years rapid progress has occurred in understanding POLRMT and elucidating the molecular mechanisms of mitochondrial transcription. Important accomplishments include development of recombinant systems that reconstitute human mitochondrial transcription in vitro, determination of the X-ray crystal structure of POLRMT, identification of distinct mechanisms for promoter recognition and transcription initiation, elucidation of the kinetic mechanism for POLRMT-catalyzed nucleotide incorporation and discovery of unique mechanisms of mitochondrial transcription inhibition including the realization that POLRMT is an off target for antiviral ribonucleoside analogs. This review summarizes the current understanding of POLRMT structure–function, mechanism and inhibition. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► The human mitochondrial RNA polymerase (POLRMT) transcribes the mitochondrial genome with the help of accessory factors. ► POLRMT is evolutionarily related to bacteriophage T7 RNAP. ► Understanding properties of POLRMT is central to comprehending the mechanism of human mitochondrial transcription.
Keywords: Mitochondrial RNA polymerase; POLRMT; mtRNAP; Transcription; Mitochondrion
Mitochondrial transcription: Lessons from mouse models by Susana Peralta; Xiao Wang; Carlos T. Moraes (pp. 961-969).
Mammalian mitochondrial DNA (mtDNA) is a circular double-stranded DNA genome of ~16.5 kilobase pairs (kb) that encodes 13 catalytic proteins of the ATP-producing oxidative phosphorylation system (OXPHOS), and the rRNAs and tRNAs required for the translation of the mtDNA transcripts. All the components needed for transcription and replication of the mtDNA are, therefore, encoded in the nuclear genome, as are the remaining components of the OXPHOS system and the mitochondrial translation machinery. Regulation of mtDNA gene expression is very important for modulating the OXPHOS capacity in response to metabolic requirements and in pathological processes. The combination of in vitro and in vivo studies has allowed the identification of the core machinery required for basal mtDNA transcription in mammals and a few proteins that regulate mtDNA transcription. Specifically, the generation of knockout mouse strains in the last several years, has been key to understanding the basis of mtDNA transcription in vivo. However, it is well accepted that many components of the transcription machinery are still unknown and little is known about mtDNA gene expression regulation under different metabolic requirements or disease processes. In this review we will focus on how the creation of knockout mouse models and the study of their phenotypes have contributed to the understanding of mitochondrial transcription in mammals. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Genetically modified mice have helped us understand mechanisms of mitochondrial gene expression. ► We review the knowledge acquired in mtDNA gene expression using mouse models. ► Tfam, Tfb1m, and Mterf family members were studied in details using mouse models. ► These models will uncover other regulators of mtDNA transcription.
Keywords: Abbreviations; HSP1 and HSP2; heavy strand promoter 1 and 2; LRPPRC; leucine rich pentatricopeptide repeat containing; LSP; light strand promoter; mtDNA; mitochondrial DNA; MTERF; mitochondrial transcription termination factor; POLRMT; mitochondrial RNA polymerase; rRNA; ribosomal RNA; tRNA; transfer RNA; TFAM; mitochondrial transcription factor A; TFB1M; mitochondrial transcription factor B1; TFB2M; mitochondrial transcription factor B2; ETC; electron transport chain; OXPHOS; oxidative phosphorylation systemmtDNA; Transcription; MTERF; TFAM; Mitochondria
The interface of transcription and DNA replication in the mitochondria by Rajesh Kasiviswanathan; Tammy R.L. Collins; William C. Copeland (pp. 970-978).
DNA replication of the mitochondrial genome is unique in that replication is not primed by RNA derived from dedicated primases, but instead by extension of processed RNA transcripts laid down by the mitochondrial RNA polymerase. Thus, the RNA polymerase serves not only to generate the transcripts but also the primers needed for mitochondrial DNA replication. The interface between this transcription and DNA replication is not well understood but must be highly regulated and coordinated to carry out both mitochondrial DNA replication and transcription. This review focuses on the extension of RNA primers for DNA replication by the replication machinery and summarizes the current models of DNA replication in mitochondria as well as the proteins involved in mitochondrial DNA replication, namely, the DNA polymerase γ and its accessory subunit, the mitochondrial DNA helicase, the single-stranded DNA binding protein, topoisomerase I and IIIα and RNaseH1. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Mitochondrial DNA replication is primed by transcription. ► An asynchronous and coupled model of mtDNA replication has been proposed. ► MtDNA is replicated by pol γ, helicase, SSB, topo and RNaseH1.
Keywords: Mitochondrial DNA replication; DNA polymerase gamma; Twinkle helicase; Mitochondrial topoisomerase; Single-stranded DNA binding protein
Mitochondrial DNA damage and its consequences for mitochondrial gene expression by Susan D. Cline (pp. 979-991).
How mitochondria process DNA damage and whether a change in the steady-state level of mitochondrial DNA damage (mtDNA) contributes to mitochondrial dysfunction are questions that fuel burgeoning areas of research into aging and disease pathogenesis. Over the past decade, researchers have identified and measured various forms of endogenous and environmental mtDNA damage and have elucidated mtDNA repair pathways. Interestingly, mitochondria do not appear to contain the full range of DNA repair mechanisms that operate in the nucleus, although mtDNA contains types of damage that are targets of each nuclear DNA repair pathway. The reduced repair capacity may, in part, explain the high mutation frequency of the mitochondrial chromosome. Since mtDNA replication is dependent on transcription, mtDNA damage may alter mitochondrial gene expression at three levels: by causing DNA polymerase γ nucleotide incorporation errors leading to mutations, by interfering with the priming of mtDNA replication by the mitochondrial RNA polymerase, or by inducing transcriptional mutagenesis or premature transcript termination. This review summarizes our current knowledge of mtDNA damage, its repair, and its effects on mtDNA integrity and gene expression. This article is part of a special issue entitled: Mitochondrial Gene Expression.► Mitochondrial DNA is susceptible to endogenous and environmental damage. ► Mitochondria lack the full cohort of nuclear DNA repair mechanisms. ► Persistent mtDNA damage poses a threat to mitochondrial gene expression. ► Mitochondrial polymerase disruption by mtDNA damage may underlie human disease and environmental toxicity.
Keywords: Mitochondrial DNA damage; DNA repair; Mitochondrial transcription; Reactive oxygen species; Mitochondrial replication; Reactive aldehydes
Mitochondrial poly(A) polymerase and polyadenylation by Jeong Ho Chang; Liang Tong (pp. 992-997).
Polyadenylation of mitochondrial RNAs in higher eukaryotic organisms have diverse effects on their function and metabolism. Polyadenylation completes the UAA stop codon of a majority of mitochondrial mRNAs in mammals, regulates the translation of the mRNAs, and has diverse effects on their stability. In contrast, polyadenylation of most mitochondrial mRNAs in plants leads to their degradation, consistent with the bacterial origin of this organelle. PAPD1 (mtPAP, TUTase1), a noncanonical poly(A) polymerase (ncPAP), is responsible for producing the poly(A) tails in mammalian mitochondria. The crystal structure of human PAPD1 was reported recently, offering molecular insights into its catalysis. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.►Mitochondrial polyadenylation regulates RNA function and metabolism. ►Mitochondrial polyadenylation occurs in higher eukaryotes. ►Human mitochondrial poly(A) polymerase (PAPD1) is a noncanonical PAP. ►The structure of PAPD1 provides molecular insights into its catalysis.
Keywords: mRNA processing; mRNA stability; RNA editing; Noncanonical poly(A) polymerase; Polynucleotide phosphorylase; Cytoplasmic polyadenylation
PNPASE and RNA trafficking into mitochondria by Geng Wang; Eriko Shimada; Carla M. Koehler; Michael A. Teitell (pp. 998-1007).
The mitochondrial genome encodes a very small fraction of the macromolecular components that are required to generate functional mitochondria. Therefore, most components are encoded within the nuclear genome and are imported into mitochondria from the cytosol. Understanding how mitochondria are assembled, function, and dysfunction in diseases requires detailed knowledge of mitochondrial import mechanisms and pathways. The import of nucleus-encoded RNAs is required for mitochondrial biogenesis and function, but unlike pre-protein import, the pathways and cellular machineries of RNA import are poorly defined, especially in mammals. Recent studies have shown that mammalian polynucleotide phosphorylase (PNPASE) localizes in the mitochondrial intermembrane space (IMS) to regulate the import of RNA. The identification of PNPASE as the first component of the RNA import pathway, along with a growing list of nucleus-encoded RNAs that are imported and newly developed assay systems for RNA import studies, suggest a unique opportunity is emerging to identify the factors and mechanisms that regulate RNA import into mammalian mitochondria. Here we summarize what is known in this fascinating area of mitochondrial biogenesis, identify areas that require further investigation, and speculate on the impact unraveling RNA import mechanisms and pathways will have for the field going forward. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Mitochondrial homeostasis is maintained by PNPASE from an intermembrane space location. ► PNPASE activities in mitochondrial RNA import and RNA processing are separable. ► Imported RNAs are required for mitochondrial genome replication, transcription, and translation. ► PNPASE regulation of mitochondrial metabolism and RNA import are thus far inseparable.
Keywords: Polynucleotide phosphorylase; PNPASE; PNPT1; Mitochondria; RNA trafficking; Oxidative phosphorylation
The role of mammalian PPR domain proteins in the regulation of mitochondrial gene expression by Oliver Rackham; Aleksandra Filipovska (pp. 1008-1016).
Pentatricopeptide repeat (PPR) domain proteins are a large family of RNA-binding proteins that are involved in the maturation and translation of organelle transcripts in eukaryotes. They were first identified in plant organelles and their important role in mammalian mitochondrial gene regulation is now emerging. Mammalian PPR proteins, like their plant counterparts, have diverse roles in mitochondrial transcription, RNA metabolism and translation and consequently are important for mitochondrial function and cell health. Here we discuss the current knowledge about the seven mammalian PPR proteins identified to date and their roles in the regulation of mitochondrial gene expression. Furthermore we discuss the mitochondrial RNA targets of the mammalian PPR proteins and methods to investigate the RNA targets of these mitochondrial RNA-binding proteins. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.Display Omitted► PPR proteins are a large family of RNA-binding proteins that regulate organelle gene expression. ► We discuss the diverse roles of mammalian PPR proteins in mitochondrial RNA metabolism. ► We discuss methods to investigate the RNA targets of mitochondrial PPR proteins.
Keywords: PPR protein; Mitochondrial RNA; RNA metabolism
Of P and Z: Mitochondrial tRNA processing enzymes by Walter Rossmanith (pp. 1017-1026).
Mitochondrial tRNAs are generally synthesized as part of polycistronic transcripts. Release of tRNAs from these precursors is thus not only required to produce functional adaptors for translation, but also responsible for the maturation of other mitochondrial RNA species. Cleavage of mitochondrial tRNAs appears to be exclusively accomplished by endonucleases. 5′-end maturation in the mitochondria of different Eukarya is achieved by various kinds of RNase P, representing the full range of diversity found in this enzyme family. While ribonucleoprotein enzymes with RNA components of bacterial-like appearance are found in a few unrelated protists, algae, and fungi, highly degenerate RNAs of dramatic size variability are found in the mitochondria of many fungi. The majority of mitochondrial RNase P enzymes, however, appear to be pure protein enzymes. Human mitochondrial RNase P, the first to be identified and possibly the prototype of all animal mitochondrial RNases P, is composed of three proteins. Homologs of its nuclease subunit MRPP3/PRORP, are also found in plants, algae and several protists, where they are apparently responsible for RNase P activity in mitochondria (and beyond) without the help of extra subunits. The diversity of RNase P enzymes is contrasted by the uniformity of mitochondrial RNases Z, which are responsible for 3′-end processing. Only the long form of RNase Z, which is restricted to eukarya, is found in mitochondria, even when an additional short form is present in the same organism. Mitochondrial tRNA processing thus appears dominated by new, eukaryal inventions rather than bacterial heritage. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► A great diversity of RNase P enzymes is found in mitochondria of different organisms. ► The RNase P of many fungi contains a highly degenerated RNA. ► Most mitochondrial RNase P enzymes, however, are composed of protein only. ► Mitochondrial 3′-end processing seems to rely exclusively on the long, eukaryal form of RNase Z.
Keywords: RNase P; RNase Z; transfer RNA; RNA processing; Mitochondria
RNA Degradation in Yeast and Human Mitochondria by Roman J. Szczesny; Lukasz S. Borowski; Michal Malecki; Magdalena A. Wojcik; Piotr P. Stepien; Pawel Golik (pp. 1027-1034).
Expression of mitochondrially encoded genes must be finely tuned according to the cell's requirements. Since yeast and human mitochondria have limited possibilities to regulate gene expression by altering the transcription initiation rate, posttranscriptional processes, including RNA degradation, are of great importance. In both organisms mitochondrial RNA degradation seems to be mostly depending on the RNA helicase Suv3. Yeast Suv3 functions in cooperation with Dss1 ribonuclease by forming a two-subunit complex called the mitochondrial degradosome. The human ortholog of Suv3 (hSuv3, hSuv3p, SUPV3L1) is also indispensable for mitochondrial RNA decay but its ribonucleolytic partner has so far escaped identification. In this review we summarize the current knowledge about RNA degradation in human and yeast mitochondria. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Expression of mitochondrially encoded genes must be tigthly regulated. ► RNA degradation is the key stage for this process in human and yeast organelles. ► Mitochondrial RNA decay in both seemingly dependent on the RNA helicase Suv3. ► Current knowledge about RNA decay in human and yeast mitochondria summarized.
Keywords: mitochondrial degradosome; RNA degradation; Suv3 helicase (SUPV3L1 hSuv3p, hSuv3, Suv3p); Dss1 ribonuclease; polynucleotide phosphorylase (PNPase)
Mechanism of protein biosynthesis in mammalian mitochondria by Brooke E. Christian; Linda L. Spremulli (pp. 1035-1054).
Protein synthesis in mammalian mitochondria produces 13 proteins that are essential subunits of the oxidative phosphorylation complexes. This review provides a detailed outline of each phase of mitochondrial translation including initiation, elongation, termination, and ribosome recycling. The roles of essential proteins involved in each phase are described. All of the products of mitochondrial protein synthesis in mammals are inserted into the inner membrane. Several proteins that may help bind ribosomes to the membrane during translation are described, although much remains to be learned about this process. Mutations in mitochondrial or nuclear genes encoding components of the translation system often lead to severe deficiencies in oxidative phosphorylation, and a summary of these mutations is provided. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Mitochondrial protein synthesis is a critical component of the oxidative phosphorylation system. ► A biochemical perspective on mitochondrial protein synthesis is provided. ► Mutations in this translational systems lead to human disease.
Keywords: Mammal; Mitochondrion; Protein synthesis; Initiation; Elongation; Termination
Regulation of mammalian mitochondrial translation by post-translational modifications by Emine C. Koc; Hasan Koc (pp. 1055-1066).
Mitochondria are responsible for the production of over 90% of the energy in eukaryotes through oxidative phosphorylation performed by electron transfer and ATP synthase complexes. Mitochondrial translation machinery is responsible for the synthesis of 13 essential proteins of these complexes encoded by the mitochondrial genome. Emerging data suggest that acetyl-CoA, NAD+, and ATP are involved in regulation of this machinery through post-translational modifications of its protein components. Recent high-throughput proteomics analyses and mapping studies have provided further evidence for phosphorylation and acetylation of ribosomal proteins and translation factors. Here, we will review our current knowledge related to these modifications and their possible role(s) in the regulation of mitochondrial protein synthesis using the homology between mitochondrial and bacterial translation machineries. However, we have yet to determine the effects of phosphorylation and acetylation of translation components in mammalian mitochondrial biogenesis. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Mitochondrial protein synthesis is highly regulated by post-translational modifications (PTMs). ► Regulation of mitochondrial translation machinery is critical for the oxidative phosphorylation. ► Dysregulation of mitochondrial translation by PTMs may lead to metabolic diseases and cancer.
Keywords: Mammalian; Mitochondrial translation; Ribosome; Post-translational modification; Phosphorylation; Acetylation
Mitochondrial translational inhibitors in the pharmacopeia by Bruce H. Cohen; Russell P. Saneto (pp. 1067-1074).
The vast majority of energy necessary for cellular function is produced in the mitochondria by the phosphorylation of ADP to ATP. Other critical mitochondrial functions include apoptosis and free-radical production. Chemical agents, including those found in the modern pharmacopeia, may impair mitochondrial function by a number of mechanisms. The mitochondria are vulnerable to environmental injury because of their complex physical structure, electrochemical properties of the inner mitochondrial membrane (IMM), dual genetic control from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) and inherent properties of the translational and transcriptional machinery. Mitochondria have evolved from alpha-proteobacteria and the residual structural similarity to bacterial translational machinery has left the mtDNA genes vulnerable to inhibition by commonly used translation-targeted antibiotics. Many of these medications cause adverse effects in otherwise healthy people, but there are also examples where particular gene mutations may predispose to increased drug toxicity. It is hoped that preclinical pharmacogenetic and functional studies of mitochondrial toxicity, along with personalized genomic medicine, will improve both our understanding of the spectrum of disease caused by inhibition of mitochondrial translation and improve the safe and effective use of antibiotics that inhibit bacterial and human mitochondrial translation. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.►Bacteria and mitochondria share similar genetic origins and the translation machinery in bacteria is a target for antibiotic effect. ►One-half antibiotic drug classes target the mitochondrial translation machinery and these targeting ribosomal function may cause signs of mitochondrial dysfunction. ►Understanding the similarity between bacterial and mitochondrial translation will assist in recognition of antibiotic toxicity. ►Other classes of drugs may also inhibit mitochondrial translation.
Keywords: Mitochondrial translation; Bacterial ribosome; Mitochondrial ribosome; Antibiotic toxicity; Mitochondrial DNA
Dynamic regulation of mitochondrial transcription as a mechanism of cellular adaptation by Erik S. Blomain; Steven B. McMahon (pp. 1075-1079).
Eukaryotes control nearly every cellular process in part by modulating the transcription of genes encoded by their nuclear genome. However, these cells are faced with the added complexity of possessing a second genome, within the mitochondria, which encodes critical components of several essential processes, including energy metabolism and macromolecule biosynthesis. As these cellular processes require gene products encoded by both genomes, cells have adopted strategies for linking mitochondrial gene expression to nuclear gene expression and other dynamic cellular events. Here we discuss examples of several mechanisms that have been identified, by which eukaryotic cells link extramitochondrial signals to dynamic alterations in mitochondrial transcription. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► OXPHOS and key biosynthetic reactions require synchronization of nuclear and mitochondrial transcription. ► The mitochondrial transcription complex responds directly to changes in cellular energy pools. ► A growing number of nuclear transcription factors also function within the mitochondria. ► Production of the nuclear-encoded mitochondrial transcription complex is tied to key cellular signaling pathways.
Keywords: Mitochondria; Transcription; POLRMT; mtRNAP; mtDNA
Matrix proteases in mitochondrial DNA function by Yuichi Matsushima; Laurie S. Kaguni (pp. 1080-1087).
Lon, ClpXP and m-AAA are the three major ATP-dependent proteases in the mitochondrial matrix. All three are involved in general quality control by degrading damaged or abnormal proteins. In addition to this role, they are proposed to serve roles in mitochondrial DNA functions including packaging and stability, replication, transcription and translation. In particular, Lon has been implicated in mtDNA metabolism in yeast, fly and humans. Here, we review the role of Lon protease in mitochondrial DNA functions, and discuss a putative physiological role for mitochondrial transcription factor A (TFAM) degradation by Lon protease. We also discuss the possible roles of m-AAA and ClpXP in mitochondrial DNA functions, and the putative candidate substrates for the three matrix proteases. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► We review the structure and function of mitochondrial matrix proteases. ► We explore the roles of the matrix proteases in regulation of mtDNA functions. ► We propose a physiological role for TFAM regulation by Lon protease.
Keywords: Matrix proteases; AAA+ ATPases; Mitochondria; mtDNA; TFAM
Nucleus-encoded regulators of mitochondrial function: Integration of respiratory chain expression, nutrient sensing and metabolic stress by Richard C. Scarpulla (pp. 1088-1097).
Nucleus-encoded regulatory factors are major contributors to mitochondrial biogenesis and function. Several act within the organelle to regulate mitochondrial transcription and translation while others direct the expression of nuclear genes encoding the respiratory chain and other oxidative functions. Loss-of-function studies for many of these factors reveal a wide spectrum of phenotypes. These range from embryonic lethality and severe respiratory chain deficiency to relatively mild mitochondrial defects seen only under conditions of physiological stress. The PGC-1 family of regulated coactivators (PGC-1α, PGC-1β and PRC) plays an important integrative role through their interactions with transcription factors (NRF-1, NRF-2, ERRα, CREB, YY1 and others) that control respiratory gene expression. In addition, recent evidence suggests that PGC-1 coactivators may balance the cellular response to oxidant stress by promoting a pro-oxidant environment or by orchestrating an inflammatory response to severe metabolic stress. These pathways may serve as essential links between the energy generating functions of mitochondria and the cellular REDOX environment associated with longevity, senescence and disease. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.►Nucleus-encoded factors control the expression mitochondrial respiratory function. ►Nucleus-encoded factors acting within mitochondria are essential for embryogenesis. ►Ablation of factors acting on nuclear respiratory genes results in a range of phenotypes. ►Nuclear coactivators governing respiratory gene expression respond to metabolic stress.
Keywords: Mitochondria; Transcription factor; Coactivator; Metabolic stress; Nucleomitochondrial interaction; Metabolism
Processing of mitochondrial presequences by Dirk Mossmann; Chris Meisinger; Vogtle F.-Nora Vögtle (pp. 1098-1106).
Mitochondrial proteins are synthesized as precursor proteins on either cytosolic or mitochondrial ribosomes. The synthesized precursors from both translation origins possess targeting signals that guide the protein to its final destination in one of the four subcompartments of the organelle. The majority of nuclear-encoded mitochondrial precursors and also mitochondrial-encoded preproteins have an N-terminal presequence that serves as a targeting sequence. Specific presequence peptidases that are found in the matrix, inner membrane and intermembrane space of mitochondria proteolytically remove the signal sequence upon import or sorting. Besides the classical presequence peptidases MPP, IMP and Oct1, several novel proteases have recently been described to possess precursor processing activity, and analysis of their functional relevance revealed a tight connection between precursor processing, mitochondrial dynamics and protein quality control. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.►We present an overview of mitochondrial preprotein import and presequence processing. ►We review recent developments in the field of mitochondrial presequence processing. ►We highlight a novel mitochondrial protein quality control mechanism.
Keywords: Mitochondrial processing peptidase MPP; Intermediate cleavage peptidase 55 Icp55; Octapeptidylpeptidase 1 Oct1; Inner membrane peptidase IMP; Protein turnover
Mitochondrial-nuclear co-evolution and its effects on OXPHOS activity and regulation by Dan Bar-Yaacov; Amit Blumberg; Dan Mishmar (pp. 1107-1111).
Factors required for mitochondrial function are encoded both by the nuclear and mitochondrial genomes. The order of magnitude higher mutation rate of animal mitochondrial DNA (mtDNA) enforces tight co-evolution of mtDNA and nuclear DNA encoded factors. In this essay we argue that such co evolution exists at the population and inter-specific levels and affect disease susceptibility. We also argue for the existence of three modes of co-evolution in the mitochondrial genetic system, which include the interaction of mtDNA and nuclear DNA encoded proteins, nuclear protein – mtDNA-encoded RNA interaction within the mitochondrial translation machinery and nuclear DNA encoded proteins-mtDNA binging sites interaction in the frame of the mtDNA replication and transcription machineries. These modes of co evolution require co-regulation of the interacting factors encoded by the two genomes. Thus co evolution plays an important role in modulating mitochondrial activity. This article is part of a Special Issue entitled: Mitochondrial Gene Expression.► Higher mtDNA mutation rate enforces co-evolution with nuclear DNA encoded factors. ► Disruption of mito-nuclear co evolution affects diseases, evolutionary processes. ► Such co-evolution affects interactions of proteins, protein–RNA and protein–DNA. ► Co evolution plays an important role in modulating mitochondrial activity.
Keywords: Mitochondria; Mitochondrial–nuclear interaction; Co evolution; Regulation