View source for 30. Mitochondrial protein synthesis, mitochondrial genome

== Learning objectives ==

* Describe the structure of the mitochondrial genome
* Does the mitochondrial genome encode all mitochondrial proteins?
* How is mitochondrial DNA inherited?
* Describe the replication of mtDNA
* Describe the transcription of mtDNA

== Mitochondria ==
Mitochondria is the powerhouse of the cell, but it also has other functions. It’s involved in programmed cell death (apoptosis), heat production, and anabolic processes in addition to its classic catabolic processes.

== Mitochondrial genome ==

=== Structure ===
The mitochondria have their own small (16 500 base pair) DNA, called the mtDNA. Unlike nuclear DNA, the mitochondrial DNA is circular and doesn’t use histones. Like the nuclear DNA, it is double-stranded. This genome is inherited only maternally.

However, this does not mean that the mitochondria are self-contained. The mitochondrial DNA does code for proteins to be used in the mitochondria, but the mitochondrial DNA does not contain the genes for all mitochondrial proteins. Many mitochondrial proteins are encoded in the nuclear DNA and transported into the mitochondria, as we saw earlier.

The mitochondrial DNA contains only 37 genes, but, unlike the nuclear DNA, it contains very little noncoding DNA and therefore has much higher gene density than nuclear DNA. There are no introns. Of these 37 genes:

* 22 code for tRNA
* 2 code for rRNA
* 13 code for proteins

These proteins are mostly components of the respiratory chain, including some of the subunits of complexes I, III, IV, and V. However, mitochondrial DNA only code for a small fraction of all the subunits of these complexes; most of them are imported from the cytosol from nuclear DNA.

The amount of mitochondrial DNA varies, depending on the size and shape of the mitochondria, and according to its needs. Mitochondria can increase their DNA content if needed; as an example, mitochondria in skeletal muscle can increase their DNA content 5 – 10 fold.

The mtDNA consists of two strands, one “heavy” strand and one “light” strand. These two strands encode different genes. The light strand encodes 1 subunit of the respiratory chain and 8 tRNAs. The heavy strand encodes the rest of the mitochondrial genes.

=== Replication of mtDNA ===
mtDNA is replicated by ''mtDNA polymerase γ''. It is a heterodimer consisting of the gene product of two genes; PolgA and PolgB, sometimes called POLG1 and POLG2, respectively. These genes are coded by nuclear DNA.

''mtDNA polymerase γ'' has 10x lower accuracy than ''DNA polymerase'', inserting the wrong nucleotide 10x more often.

Two other proteins are needed for replication: Twinkle and mitochondrial SSB. Twinkle is a 5′ -> 3′ helicase, while mitochondrial SSB binds to the single-stranded DNA. These are also encoded in nuclear DNA.

=== Transcription of mtDNA ===
mtDNA is transcribed by ''mitochondrial RNA polymerase'', which is encoded by nuclear DNA. Mitochondrial mRNA has no 5′ cap, but it does have the poly-A tail at the 3′ end.

Mitochondria have their own ribosomes, which translate the mitochondrial mRNA.

== Mitochondria and aging ==
The respiratory chain is the major source of reactive oxygen species in the cell, meaning that the mtDNA is subject to high levels of oxidative stress. This has lead to a theory that accumulating mitochondrial damage due to oxidative stress progressively decreases ATP production, thereby causing aging.

Mitochondrial ''superoxide dismutase'' neutralizes these reactive oxygen species. Mice deficient in this enzyme die earlier than wildtype mice.

Mice with defect gene for ''mtDNA polymerase γ'' age much quicker, also indicating the mitochondria’s role in aging.

== Summary ==

* Describe the structure of the mitochondrial genome
** It is small, circular, double-stranded, and doesn’t use histones
** It codes for tRNA, rRNA, and only 13 proteins
** It contains no introns and very little non-coding DNA
** The heavy strand encodes for most
* Does the mitochondrial genome encode all mitochondrial proteins?
** No, the vast majority of mitochondrial proteins are encoded in the nuclear DNA and imported
* How is mitochondrial DNA inherited?
** Maternally only
* Describe the replication of mtDNA
** Replicated by ''mtDNA polymerase γ'', Twinkle (a helicase) and mitochondrial SSB
** This polymerase has much lower accuracy than nuclear ''DNA polymerase''
* Describe the transcription of mtDNA
** Transcribed by ''mitochondrial RNA polymerase''
** Mitochondrial mRNA has no 5′ cap, but it has poly-A tail at the 3′ end

[[Category:Biochemistry 1 lectures]]