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).