Transcript Mitochondrial DNA

?
?
Origin of mitochondria and chloroplasts:
Both mitochondria and chloroplasts are believed to be derived from
endosymbiotic bacteria.
Endosymbiotic bacteria = free-living prokaryotes that invaded ancestral
eukaryotic cells and established a mutually beneficial relationship.
Many required mitochondria and chloroplast proteins also are coded by
nuclear genes.
numt = nuclear mtDNA (mtDNA transposed to the nucleus)
Time-line of life on earth
Origin of life
Oxygen appears
Multicellular Cambrian
life explosion
First land
plants
First
vertebrates
3800MY
2500MY
1000MY 530MY
410MY
Origin of Eukaryotic Diversity
Organelle genomes
Genome
Size & Organization
Plant plastid
150 kb circle
Plant mitochondria 150 – 2000 kb
multipartite
Human
mitochondria
17 kb circle
saccharomyces
mitochondria
75 kb circle
Encode only a subset of genes required to elaborate a functional organelle
rRNAs, tRNAs, ribosomal proteins, membrane-associated respiratory or
photosynthetic components
Other components encoded by nuclear genome, translated in the cytosol and
imported into the organelle
10% of nuclear genes devoted to mitochondrial function; 15% of nuclear genes
devoted to plastid function
Associated with proteins and organized into structures called nucleoids (not the
same as nucleosomes found in nuclear chromatin)
Eukaryotes Organelle-Genomes
• Ribosomal RNA sequences suggests that plant plastids
share common ancestor with modern Cyanobacteria such
as Synechococcus lividus
• Mt-rRNA share greatest homology with members of
alpha-group of proteobacteria which includes intracellular
parasites (Agrobacterium, Rhizobium)
• Mitochondria make up some 80% of the
volume of the cone cell photoreceptors of
the eye and 40% of the volume of heart
muscle cells.
Mitochondria are essential for oxidative
phosphorylation (make ATP)
Mitochondria are essential for oxidative
phosphorylation (make ATP)
•
•
•
•
•
•
•
•
However they play important roles in most other metabolic functions of the
cell:
* Pyrimidine synthesis
* Heme synthesis (red blood precursor cells)
* Amonia detoxification (liver)
* Cholesterol metabolism
* Sex hormone synthesis
* Free radical production and detoxification
* Apoptosis
• In fact out of the 3000 genes required to
make a mitochondrion only 100 are
concerned with making ATP.
(human: 2-10 mtDNA per mitochondrion)
Chloroplast DNA-Microscopic Image
• Electron microscopic image
of a circular DNA molecule
isolated from a soybean
chloroplast (a ctDNA)
N.M. Chu, K.K. Tewari, 1982
1 µm
.
Fig. 15.2, mtDNA replication
Transcription of the mtDNA genome:
•
mRNAs from the mtDNA are synthesized and translated in the
mitochondria.
•
Gene products encoded by nuclear genes are transported from the
cytoplasm to the mitochondria.
•
Mammalian mtDNA is unusual as it is transcribed as a single large
RNA molecule and then cleaved to produce mRNAs, tRNAs, and
rRNAs before they are processed.
•
Most mtDNA genes are separated by tRNAs that signal transcription
termination.
No coded stop codons
Mitochondrial code
Universal code
Wobble
Wobble rules:
G
C
A
U
U/C
G
U
A/G
32 tRNAs required
More Wobble in mitochondria
22 tRNAs required
Fig. 15.3, Physical map of the human mtDNA
?
Mitochondrial DNA mutations in human genetic disease (Wallace
Sci. Amer. 277:40)
Examples of maternally inherited human mtDNA defects:
•
Leber’s hereditary optic neuropathy (LHON), OMIM-535000
•
•
•
Kearns-Sayre Syndrome, OMIM-530000
•
•
•
Midlife adult blindness from optic nerve degeneration.
Mutations in ND1, ND2, ND4, ND5, ND6, cyt b, CO I, CO II, and
ATPase 6 inhibit electron transport chain.
Paralysis eye muscles, accumulation of pigment and
degeneration of the retina, and heart disease.
Deletion of mtDNA tRNAs.
Myoclonic epilepsy & ragged-red fiber disease (MERRF), OMIM545000
•
•
Spasms and abnormal tissues, accumulation of lactic acid in the
blood, and uncoordinated movement.
Nucleotoide substitution in the mtDNA lysine tRNA.
Most individuals with mtDNA disorders possess a mix of normal and
mutant mtDNA, therefore severity of diseases varies.
Mitochondrial DNA mutations in human genetic disease (Wallace
Sci. Amer. 277:40)
Mitochondrial DNA polymorphisms track human
migrations
(Wallace Sci. Amer. 277:40)
All humans descend from a small group of Africans
This group originated in central Africa ~200,000 years ago
The founding group was small (102-104 people)
Descendants of this group replaced all other hominids everywhere in the world
Maternal effect:
Some maternal phenotypes are produced by the nuclear genome rather
than the mtDNA/cpDNA genomes.
•
Proteins or mRNA (maternal factors) deposited in the oocyte prior
to fertilization.
•
Genes for maternal factors occur on nuclear chromosomes; no
mtDNA is involved
•
e.g., shell coiling in the snail Limnaea peregra.
•
Determined by a pair of nuclear alleles; D produces dextral
(right-handed) coiling, d produces sinistral (left-handed)
coiling.
•
Shell coiling always is determined by the maternal genotype,
not the alleles that the progeny carry or maternal phenotype.
•
If coiling were controlled by an extranuclear gene, progeny
would always have the same phenotype as the mother.
•
Cause-mother snail deposits products in the egg that regulate
orientation of the mitotic spindle and direction of cell cleavage.
Fig. 15.14
dextral
sinistral
*****dextral *****
*****dextral *****
Plant Cell
Higher Plant Chloroplasts
Fig. 15.5
cpDNA of rice
Examples of non-Mendelian inheritance:
•
Variegated-shoot phenotypes in four o’clocks
Mixed chloroplasts
White/green
Mutant chloroplast
White
non-photosynthetic
Normal chloroplast
Green
photosynthetic
Fig. 15.6b
Fig. 15.7
Chloroplasts are inherited
via the seed cytoplasm
3 types of eggs (female):
Normal
Mutant
Mixed
Assumption:
Pollen (male) contributes
no information
The search for new antimalarial drugs
• Malaria is one of the leading causes of morbidity and mortality in the
tropics.
• 300 to 500 million estimated clinical cases and 1.5 million to 2.7 million
deaths per year.
• Nearly all fatal cases are caused by Plasmodium falciparum.
• The parasite's resistance to conventional antimalarial drugs such as
chloroquine is growing at an alarming rate.
•P. falciparum has a plastidlike organelle, called the apicoplast,
acquired by endosymbiosis of an alga.
Jomaa et al. (1999)
Apicoplast contains enzymes found in plant and bacterial, but not
animal metabolic pathways.
•Potential target for antimalerial drugs:
DOXP reductoisomerase
Endosymbiosis