ABSTRACT
Introduction ............................................................................ 97 General Features of Human mtDNA ................................. 100
Structure, Copy Number, and Organization ............. 100 Gene Content, Codon Usage, and Decoding
Mechanism ........................................................ 105 Transmission ............................................................... 109
Transmission of the Mitochondrial Genome .. 109 Transmission of mtDNA Sequence Variants.. 110
Transcription of mtDNA...................................................... 113 Initiation of Transcription .......................................... 113
cis-Acting Elements.......................................... 113 trans-Acting Factors ......................................... 115
Elongation and Termination of Transcription .......... 120
Processing of Primary Transcripts ............................ 123 Post-Transcriptional Modifications ............................ 130
Modifications of tRNA Molecules .................... 130 Modifications of rRNA and mRNA
Molecules ............................................. 134 Mitochondrial Protein Synthesis ........................................ 135
Mitochondrial tRNAs .................................................. 135 Mitochondrial Ribosomes............................................ 137 Initiation of Translation ............................................. 141 Elongation of Translation ........................................... 146 Termination of Translation......................................... 148
Replication of mtDNA.......................................................... 149 General Features of Replication ................................ 149 The Strand-Asynchronous Model of Replication ...... 151
Basic Mechanism.............................................. 151 Initiation of H-Strand Synthesis..................... 153 Initiation of L-Strand Synthesis ..................... 155
The Strand-Synchronous Model of Replication ........ 156 Maturation of the Daughter mtDNA Molecules ....... 159 trans-Acting Factors Involved in Replication............ 160
Mitochondrial RNases ...................................... 160 DNA Polymerase γ............................................ 163 Mitochondrial Single-Stranded
Binding Protein................................... 167 Mitochondrial DNA Helicase and Possible
Primase................................................ 168 Mitochondrial DNA Topoisomerases ............... 170 Mitochondrial DNA Ligase .............................. 173
Control of mtDNA Copy Number ....................................... 175 Variations in mtDNA Copy Numbers........................ 175 Transcriptional Control of Nuclear Genes
Encoding Mitochondrial Factors...................... 177 Control of mtDNA Copy Number by cis-and
trans-Acting Factors ......................................... 179 Multiple Roles for TFAM............................................ 181
Concluding Remarks............................................................ 185 References............................................................................. 186
INTRODUCTION
Mitochondria are essential eukaryotic organelles whose principal function is to generate ATP through the process of oxidative phosphorylation (1). They also house many additional metabolic pathways and are involved in Ca2+ homeostasis, apoptosis, and thermogenesis (2-4). Mitochondria possess two membranes: an outer membrane, which encloses the organelle and separates it from the cytosol, and a larger inner membrane. The latter can be further divided into two contiguous components: the inner boundary membrane that apposes the outer membrane, and the cristae membrane that projects into the matrix compartment (5,6). The five multisubunit complexes (I through V) of the oxidative phosphorylation system required for ATP synthesis are embedded in the cristae membrane (7).
