Info

Eukaryotic

Eubacterial

Mitochondrial

Chloroplast

Characteristic

Genome

Genome

Genome

Genome

Genome consists of double-stranded DNA

Yes

Yes

Yes

Yes

Circular

No

Yes

Most

Yes

Histone proteins

Yes

No

No

No

Size

Large

Small

Small

Small

Single molecule per genome

No

Yes

Yes in animals No in some plants

Yes

Pre-mRNA introns

Common

Absent

Absent

Absent

Group I introns

Present

Present

Present

Present

Group II introns

Absent

Present

Present

Present

Polycistronic mRNA

Uncommon

Common

Present

Common

5' cap added to mRNA

Yes

No

No

No

3' poly(A) tail added to mRNA

Yes

No

Some in animals

No

Shine-Dalgarno sequence in 5'untranslated region of mRNA

No

Yes

Rare

Some

Nonuniversal codons

Rare

Rare

Yes

No

Extended wobble

No

No

Yes

No

Translation inhibited by tetracycline

No

Yes

Yes

Yes

from eubacterial ancestors more than a billion years ago. Through time, the genomes of the endosymbiont have undergone considerable evolutionary change and have evolved characteristics that distinguish them from contemporary eubacterial and eukaryotic genomes.

The Intergenomic Exchange of Genetic Information

Many proteins found in modern mitochondria and chloro-plasts are encoded by nuclear genes, which suggests that much of the original genetic material in the endosymbiont has probably been transferred to the nucleus. This assumption is supported by the observation that some DNA sequences normally found in mtDNA have been detected in nuclear DNA of some strains of yeast and maize. Likewise, chloroplast sequences have been found in the nuclear DNA of spinach Furthermore, the sequences of nuclear genes that encode organelle proteins are most similar to their eubacte-rial counterparts.

There is also evidence that genetic material has moved from chloroplasts to mitochondria. For example, DNA fragments from the 16S rRNA gene and two tRNA genes that are normally encoded by cpDNA have been found in the mtDNA of maize. Sequences from the gene that encodes the large subunit of RuBisCO, which is normally encoded by cpDNA, are duplicated in maize mtDNA. And there is even evidence that some nuclear genes have moved into mito-chondrial genomes. The exchange of genetic material between the nuclear, mitochondrial, and chloroplast genomes has given rise to the term "promiscuous DNA" to describe this phenomenon. The mechanism by which this exchange takes place is not entirely clear.

Mitochondrial DNA and Aging in Humans

Symptoms of many human genetic diseases caused by defects in mtDNA first appear in middle age or later and increase in severity as people age. One hypothesis to explain the late onset and progressive worsening of mitochondrial diseases is related to the decline in oxidative phosphorylation with aging.

Oxidative phosphorylation is the process that generates ATP, the primary carrier of energy in the cell. This process takes place on the inner membrane of the mitochondrion and requires a number of different proteins, some encoded by mtDNA and others encoded by nuclear genes. Oxidative phosphorylation normally declines with age and, if it falls below some critical threshold, tissues do not make enough ATP to sustain vital functions and disease symptoms appear. Most people start life with an excess capacity for oxidative phosphorylation; this capacity decreases with age, but most people reach old age or die before the critical threshold is passed. Persons born with mitochondrial diseases carry mutations in their mtDNA that lower their oxidative phos-phorylation capacity. At birth, their capacity may be sufficient to support their ATP needs but, as their oxidative phosphorylation capacity declines with age, they cross the critical threshold and begin to experience symptoms. These symptoms usually first appear in tissues that are most critically dependent on mitochondrial energy: the central nervous system, heart and skeletal muscle, pancreatic islets, kidneys, and the liver.

Why does oxidative phosphorylation capacity decline with age? One possible explanation is that damage to mtDNA accumulates with age; deletions and base substitutions in mtDNA increase with age. For example, a common 5000-bp deletion in mtDNA is absent in normal heart muscle cells before the age of 40, but afterward this deletion is present with increasing frequency. The same deletion is found at a low frequency in normal brain tissue before age 75 but is found in 11% to 12% of mtDNAs in the basal ganglia by age 80. People with mtDNA genetic diseases may age prematurely because they begin life with damaged mtDNA.

The mechanism of age-related increases in mtDNA damage is not yet known. Oxygen radicals, highly reactive compounds that are natural by-products of oxidative phosphorylation, are known to damage DNA (see p. 000 in Chapter 17). Because mtDNA is physically close to the enzymes taking part in oxidative phosphorylation, it may be more prone to oxidative damage than nuclear DNA. When mtDNA has been damaged, the cell's capacity to produce ATP drops. To produce sufficient ATP to meet the cell's energy needs, even more oxidative phosphorylation must occur, which in turn may stimulate further production of oxygen radicals, leading to a vicious cycle.

Significantly elevated levels of mtDNA defects have been observed in some patients with late-onset degenerative diseases, such as diabetes mellitus, ischemic heart disease, Parkinson disease, Alzheimer disease, and Huntington disease. All of these diseases appear in middle to old age and have symptoms associated with tissues that critically depend on oxidative phosphorylation for ATP production. However, because Huntington disease and some cases of Alzheimer disease are inherited as autosomal dominant conditions, mtDNA defects cannot be the primary cause of these diseases, although they may contribute to their progression.

Connecting Concepts Across Chapters 9

This chapter is about the unique properties of organelle DNA, which is part of the cytoplasm and usually exhibits uniparental inheritance. A unifying theme has been that mitochondria and chloroplasts evolved from free-living eubacteria that entered into an endosymbiotic relation with the eukaryotic cells in which they are found. Endosymbiosis helps to explain many of the characteristics of mitochondrial DNA and chloroplast DNA, which resemble eubacterial DNA more than they do nuclear eukaryotic DNA. However, not all aspects of mtDNA and cpDNA are similar to eubacterial DNA; organelle DNA has a number of properties that are unique.

Another prominent theme that runs through this chapter is that cpDNA and mtDNA display a bewildering diversity of variation in size and organization. The reason for this variation is unknown, but the variation makes summarizing mitochondrial and chloroplast genomes difficult.

Traits encoded by mitochondrial and chloroplast genes are inherited in a very different manner from those encoded by nuclear genes. Because organelle DNA is located in the cytoplasm, the traits that it encodes exhibit cytoplasmic inheritance and are typically inherited from a single parent, most often the mother. Many traits encoded by mtDNA and cpDNA exhibit phenotypic variation among progeny of a single cross and even among cells and tissues within an individual organism; the latter occurs when there are two or more genetic variants in a single cell and random segregation of the organelles in cell division produces cells with different proportions of the two types of DNA.

Understanding the inheritance of mitochondrial- and chloroplast-encoded traits builds on earlier discussions of uniparental inheritance in Chapter 5 and biparental inheritance (with which it is contrasted) in Chapter 3. Material in the present chapter is closely linked to information on DNA structure and organization found in Chapters 10 and 11 and to discussions of replication, transcription, RNA processing, and translation found in Chapters 12 through 15. Molecular techniques described in this chapter are covered more thoroughly in Chapter 18. The use of mtDNA in evolutionary studies will be discussed in more detail in Chapter 23.

CONCEPTS SUMMARY]_

• Mitochondria and chloroplasts are eukaryotic organelles that possess their own DNA. Traits encoded by mtDNA and cpDNA exhibit cytoplasmic inheritance and usually are inherited from a single parent, most often the mother. Random segregation of organelles in cell division may produce phenotypic variation among cells within a single individual and among the offspring of a single female.

• The endosymbiotic theory proposes that mitochondria and chloroplasts originated as free-living prokaryotic (specifically eubacterial) organisms that entered into a beneficial association with eukaryotic cells. Similarities in the gene sequences of organelle and eubacterial DNA support a eubacterial origin for mitochondrial and chloroplast DNA.

• The mitochondrial genome usually consists of a single, circular DNA molecule that lacks histone proteins, although plants may have multiple circular molecules. Mitochondrial DNA varies in size among different groups of organisms; most of this variation is due to noncoding DNA. Each cell contains many copies of mtDNA.

• The organization of genes in the mitochondrial genome differs among organisms. Ancestral mitochondrial genomes typically have characteristics of eubacterial genomes, including eubacterial-like ribosomes, a complete or almost complete set of tRNA genes, few introns, little noncoding DNA between genes, genes organized into eubacterial-like clusters, and the use of only universal codons. Derived mitochondrial genomes are smaller and contain fewer genes. Their rRNA genes and ribosomes differ from those found in eubacteria, and they use some nonuniversal codons.

• Human mtDNA is highly economical, with few noncoding nucleotides. Fungal and plant mtDNAs contain much noncoding DNA between genes, introns within genes, and extensive 5' and 3' untranslated regions. Most plant mitochondrial genomes contain one or more large direct repeats, which may recombine to produce smaller or larger DNA molecules.

• Mitochondrial DNA is synthesized throughout the cell cycle, and its synthesis is not coordinated with the replication of nuclear DNA.

• The transcription of mitochondrial genes varies among different organisms. Messenger RNAs produced by the transcription of mtDNA are not capped at their 5' ends; poly(A) tails are added to the 3' ends of some animal mRNAs, but these tails are different from the poly(A) tails found on nuclear-encoded mRNAs.

• Antibiotics that inhibit eubacterial ribosomes also inhibit mitochondrial ribosomes. Protein synthesis in mitochondria is initiated at AUG start codons by N-formylmethionine and employs eubacterial-like elongation factors. Many mitochondrial genomes encode a limited number of tRNAs, with relaxed codon-anticodon pairing rules and extended wobble.

• Comparisons of mtDNA sequences suggest that mitochondria evolved from a eubacterial ancestor. Vertebrate mtDNA exhibits rapid change in sequence but little change in gene content and organization. Plant mtDNA exhibits little change in sequence but much variation in gene content and organization.

• Chloroplast genomes consist of a single, circular DNA molecule that varies little in size and lacks histone proteins. Each plant cell contains multiple copies of cpDNA.

• Most chloroplast chromosomes possess large inverted repeats; some chloroplast genes contain introns.

• Transcription and translation are similar in chloroplasts and eubacteria: most chloroplast genes are transcribed as polycistronic units, their mRNAs are not capped, no poly(A)

tails are added, and they possess a Shine-Dalgamo ribosome-binding sequence.

• Chloroplast DNA sequences are most similar to those in cyanobacteria. Chloroplast DNA sequences tend to evolve slowly.

• Through evolutionary time, many mitochondrial and chloroplast genes have moved to nuclear chromosomes. In some plants, there is evidence that copies of chloroplast genes have moved to the mitochondrial genome.

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