John McCullagh January 7, 2008
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Though we are happily not aware of it most of the time, we are all familiar with parasites living in our bodies – especially, as now, in winter, when it seems we are constantly assaulted with a host of viruses and bacteria living off us.
 

 

Eventually they die, or leave and we recover our health. But it is now believed that at least one – a very, very long time ago – survived and became part of us, indeed an essential and integral part of us.

In cell biology mitochondria are membrane-enclosed organelles found in most eukaryotic cells. Their origin is unclear, but according to the endosymbiotic theory, mitochondria are thought to be descended from ancient bacteria.  These organelles range from 1-10 micrometers (μm) in size.  Mitochondria are sometimes described as “cellular power plants” because they generate most of the cell’s supply of adenosine triphosphate (ATP), used as a source of chemical energy.  In addition mitochondria are involved in a range of other processes, such as signalling, cellular differentiation and cell death, as well as the control of the cell cycle and cell growth.  Finally, mitochondria have been implicated in several human diseases and may play a role in the aging process.

In humans, the mitochondria may contain about 615 distinct proteins depending on the tissue of origin.  Although most of a cell’s DNA is contained in the cell nucleus, the mitochondrion has its own independent genome.  Further, its DNA shows substantial similarity to bacterial genomes.  These characteristics allow the mitochondrion to play a critical role in cellular processes.

Mitochondria are found in nearly all eukaryotes. They vary in number and location according to cell type.  Substantial numbers of mitochondria are in the liver, with about 1000-2000 mitochondria per cell making up 1/5th of the cell volume. The mitochondria can be found nestled between myofibrils of muscle or wrapped around the sperm flagellum.  Often they form a complex 3D branching network inside the cell with the cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as well. 

A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task.  This is done by oxidizing the major products of glycolysis, pyruvate and NADH, which are produced in the cytosol.  This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen.  When oxygen is limited, the glycolytic products will be metabolized by anaerobic respiration, a process that is independent of the mitochondria.  The production of ATP from glucose has an approximately 13-fold higher yield during aerobic respiration compared to anaerobic respiration.

Mitochondria have many features in common with prokaryotes. They contain ribosomes and DNA and are formed only by the division of other mitochondria. It is for this reason that they are believed to be originally derived from endosymbiotic prokaryotes.  Studies of mitochondrial DNA, which is often circular and employs a variant genetic code, show that their ancestor, the so-called proto-mitochondrion, was a member of the Proteobacteria.  In particular, the pre-mitochondrion was probably related to the rickettsia.  However, the exact position of the ancestor of mitochondria among the alpha-proteobacteria remains controversial. 

The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.  It suggests that mitochondria descended from specialized bacteria (probably purple non-sulfur bacteria) that somehow survived endocytosis by another cell, and became incorporated into the cytoplasm.  The ability of symbiant bacteria to conduct cellular respiration in host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage.  Similarly, host cells with symbiotic bacteria capable of photosynthesis would also have had an advantage. The incorporation of symbiotes could have increased the number of environments in which the cells could survive. This symbiotic relationship probably developed about 2 billion years ago.  Some evidence that mitochondria have their origin from bacteria is that their ribosomes are more like those from bacteria, 70S size, in contrast to the 80S ribosomes found elsewhere in the cell.

There are no primitive eukaryotes today that lack mitochondria. The endosymbiosis with mitochondria may have played a critical part in the survival advantage of eukaryotic cells.

The human mitochondrial genome is a circular DNA molecule of about 16 kilobases.  It encodes 37 genes: 13 for subunits of respiratory complexes I, III, IV, and V, 22 for mitochondrial tRNA, and 2 for rRNA.  One mitochondrion can contain 2-10 copies of its DNA.

Mitochondria replicate their DNA and divide mainly in response to the energy needs of the cell. In other words, their growth and division is not linked to the cell cycle.  When the energy needs of a cell are high, mitochondria grow and divide.  When the energy use is low, mitochondria are destroyed or become inactive.  At cell division, mitochondria are distributed to the daughter cells essentially randomly during the division of the cytoplasm.  Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can also fuse with other mitochondria.

Mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an egg cell by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus.  In contrast, the mitochondria, and therefore the mitochondrial DNA, usually come from the egg only.  The sperm’s mitochondria enter the egg but do not contribute genetic information to the embryo.  Instead, paternal mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.  The egg cell contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism.  Mitochondria are, therefore, in most cases inherited down the female line, known as maternal inheritance.  This mode is seen in most organisms including all animals.  However, mitochondria in some species can sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and yew trees.  It has also been suggested that it occurs at a very low level in humans.

Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of mitochondria, although a single mitochondrion can contain 2-10 copies of its DNA. For this reason, mitochondrial DNA usually is thought to reproduce by binary fission. What recombination does take place maintains genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in mitochondrial DNA. The enzymes necessary for recombination clearly are present in mammalian cells.  Further, evidence suggests that animal mitochondria can undergo recombination.  The data are a bit more controversial in humans, although indirect evidence of recombination exists.  If recombination does not occur, the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the evolutionary history of populations.

The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for scientists involved in population genetics and evolutionary biology.  Because the entire mitochondrial DNA is inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can be represented as a gene tree.  Patterns in these gene trees can be used to infer the evolutionary history of populations.  The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a recent date for mitochondrial Eve.  This is often interpreted as strong support for a recent modern human expansion out of Africa.  Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically modern humans.

However, mitochondrial DNA reflects the history of only females in a population, and so may not represent the history of the population as a whole. This can be partially overcome by the use of patrilineal genetic sequences, such as the non-recombining region of the Y-chromosome.  In a broader sense, only studies that also include nuclear DNA can provide a comprehensive evolutionary history of a population.  However, genetic recombination means that these studies can be difficult to analyze.

Given the role of mitochondria as the cell’s powerhouse, there may be some leakage of the high-energy electrons in the respiratory chain to form reactive oxygen species. This can result in significant oxidative stress in the mitochondria with high mutation rates of mitochondrial DNA.  A vicious cycle is thought to occur as oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further oxidative stress. A number of changes occur to mitochondria during the aging process. Tissues from elderly patients show a decrease in enzymatic activity of the proteins of the respiratory chain.  Large deletions in the mitochondrial genome can lead to high levels of oxidative stress and neuronal death in Parkinson’s disease.  Hypothesized links between aging and oxidative stress are not new and were proposed over 50 years ago; however, there is much debate over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in mice demonstrated no increase in reactive oxygen species despite increasing mitochondrial DNA mutations, suggesting the aging process is not due to oxidative stress. As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yet been settled.

Some human diseases are related to mitochondrial enzymes. Other diseases not directly linked to mitochondrial enzymes may feature dysfunction of mitochondria. These include schizophrenia, bipolar disorder, dementia, Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, and diabetes mellitus.  The common thread linking these seemingly-unrelated conditions is cellular damage, causing oxidative stress and the accumulation of reactive oxygen species.  These oxidants then damage the mitochondrial DNA, resulting in mitochondrial dysfunction and cell death.

 

 

 

 

 

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