LHON Cause

What is the cause of Leber Hereditary Optic Neuropathy?

LHON is a genetic condition.  That means the underlying cause is a change or mutation in the information inherited from the affected person’s parents.

LHON cannot be passed from one person to another like a common cold or the Flu.

This page describes the way the body releases energy from food, concentrating on the proteins inside Mitochondria.

the underlying cause of LHON is one or more changes or mutations in genes which tell your body how to make these proteins.

Although doctors know that there is some link between a LHON-causing mutation and the symptoms of LHON, they do not know exactly how they are linked.

Doctors cannot yet explain why so many people carry a LHON causing mutation but never develop LHON.

Doctors cannot explain why some people carrying a LHON mutation suddenly lose eyesight, or why it affects one eye first, then the other.

Doctors can examine the eyes of someone who has LHON, and they see changes during the Acute Phase.

Doctors see that the Retinal Nerve Fiber Layer in an affected eye is much thinner.  They can see that Retinal Ganglion Cells have been affected, swollen, gone dormant and may even have died.

Doctors are trying to find out what factor triggers the loss of eyesight – see the pages on Possible Triggers and the Threshold Proposal. 

 

What happens in Mitochondria?

Your body is made up of a huge number of cells.  Al most all of these cells have many hundreds of things called Mitochondria (pronounced Mite-Oh-Kon_dree_Ah).   Inside the mitochondria, the body runs a series of chemical reactions to release energy from the food you eat.  The energy is used to make a chemical called ATP.

ATP is the “fuel” of the cell. When the cell needs to do some work, for example a nerve cell needs to send a nerve impulse, it splits ATP to release the energy.

Simplified diagram of a cell

 

 

The cell needs to get its energy from carbohydrate or fat.  It starts the process of breaking up the carbohydrate or fat,  but can only release a small amount of energy by itself.

To get all of the energy out of the food efficiently, the cell switches to chemical processes going on inside Mitochondria. These chemical processes break down the carbohydrate or fat and produce chamicals called NADH and FADH.

The cell then needs to release the stored energy in NADH and FADH in a controlled way and link or “couple” this to creating ATP, thre “fuel” used by the cell.

The mechanism for this is the Electron Transport Chain – the 5 protein complexes embedded in the Inner Mitochondrial Membrane.

The checmical processes that release enrgy from food are carried out by a series of very large proteins.  Scientists have several different chemical names for these proteins, but often they are just called Complex I, Complex II, Complex III, Complex IV and Complex V.

Working together, these proteins are called the Electron Transport Chain or ETC.  That is because they work together to move electrons around like a very tiny electric current, and use the energy to create ATP.

There are complicated biological processes going on inside Mitochondria to break up carbohydrates and release the energy stored inside them. This page will ignore them, and describe what happens to the end result.

The processes inside Mitochondria end up generating lots of a chamical called NADH and also a chemical called FADH.  These are the chemicals that drive the complex proteins of the Electron Transport Chain .

Every Mitochondrion is made up of two membranes, one inside the other.  These are imaginatevely called the Outer Mitochondrial Membrane and the Inner Mitochondrial Membrane.

The Outer Membrane is usually drawn as a simple porous container like a sausage skin.

The Inner Membrane has a lot of folds, and is packed with many, many copies of the proteins of the Electron Transport Chain grouped closely together as shown in the diagram.

This is a diagram of a tiny section of the Inner Mitochondrial Membrane, showing just one instance of the Electron Transport Chain.

Below the Membrane is the inside or matrix of the Mitochondrion.

Above the Membrane is the space between the Inner Mitochondrial Membrane and the Outer Mitochondrial Membrane.

I = Complex I or NADH Dehydrogenase or NADH-Q-Oxidoreductase

II = Complex 2 or Succinate-Q-Reductase

III = Complex 3 or Q-Cytochrome-C-Oxidoreductase

IV = Complex 4 or Cytochrome C Oxidase

V = ATP Synthase

Uq – Ubiquinone or Co-enzyme Q10

CyC = Cytochrome C

 

Diagram of the protein complexes of the Electron Transport Chain embedded in the Inner Mitochondrial Membrane

 

Complex I is very large and roughly L-shaped. One branch of the L projects into the Mitochondrion and one branch is embedded in the Inner Mitochondrial Membrane.  It has a molecule of Co-enzyme Q10, also called Ubiquinol, bound into the structure to help it store and use the energy of electrons.

Complex I picks up high energy electrons from NADH inside the Mitochondrion  They pass along the branch and are captured by the Ubiquinone molecule, then along the membrane branch.

At the end of the membrane branch of Complex I, the electrons are passed to a molecule of Ubiquinone “floating” in the membrane.

As electrons “flow” along Complex I, the energy and protein shape changes “pump” Hydrogen (as protons) across the Mitochondrial Membrane.

 

The Ubiquinone moves inside the membrane and passes the electron to Comjplex III.

Complex II takes electrons from FADH and also passes them to free-floating molecules of Ubiquinone. the Ubiquinone molecules pass the electrons on to Complex III.

Again, as electrons travel across Complex III the energy and protein shape changes “pump” Hydrogen as protons out of the Mitochondrion.

Complex III passes the electrons on to Cytochrome C, and this in turn passes them to Complex IV.

Complex IV uses the electrons to form water molecules from Oxygen inside the Mitochondrion. Again some of the energy is used to “Pump” Hydrogen as protons out of the Mitochondrion.

All of this Hydrogen (proton) pumped out of the Mitochondrion creates a “gradient” or electrical charge across the Mitochondrial Membrane. Complex V allows the Hydrogen (protons) to flow back into the Mitochondrion, using the energy to form ATP.

In this diagram the red arrows indicate the “flow” of electrons and the blue arrows indicate the “flow” of Hydrogen ions or Protons.

 

Very simplified diagram of the proteins in the Electron Transport Chain generating an electrical gradient and using it to form ATP

The Mitochondrial Chromosome

The complex proteins of the Electron Transport Chain are built up from many smaller subunits.  There is a gene – a piece of DNA – telling the cell how to build each of these subunits.

Most of these genes are held in the cell nucleus, but a few of the genes are inside the Mitochondria, on the Mitochondrial Chromosome.

Each gene can be drawn up as a long sequence of letters.  This sequence tells the protein-building mechanism of the cell how to build the protein.

Although there are only four possible letters, A, C, G and T, they can be put together in a large number of combinations.

The Mitochondrial Chromosome is a sting of DNA with 16569 “letters”.  Scientists call each letter position a “b ase pair” or bp for short.

The Mitochondrial Chromosome is usually shown as a circle, with position 1 joined to position 16569.

The Mitochondrial Chromosome  holds genes for a small number of the essential subunits of these proteins:

Complex I subunits ND1, ND2, ND3, ND4, ND4L, ND5 and ND6.

Complex III – Cytochrome B.

Complex IV- Subunits COX1, COX2 and COX3

Complex V – ATP Synthase Subunit 6 and Subunit 8.

The LHON Mutations

LHON is caused by one or more changes in the Mitochondrial Chromosome.

Each change, or mutation, is a change to the “letter” in a particular position on the chromosome.

The mutations are identified by combining

The Chromosome name,

The Gene name

The position or base pair number

The original or “wild-type” letter

The new mutated letter.

For example, the commonest LHON causing mutation is MT-ND4 11778 G>A.

This is often written in a shorter form, just G11778A.

This mutation means that the protein-buildijng mechanism gets alightly wrong instructions for building the ND4 subunit of Complex I.   The “mutated” protein subunit will not have exactly the same shape or chemical properties as the original.

This mutation means that the whole Complex I structure does not do its job properly in the Mitochondrial Membrane.

When one of the protein complexes is affected by a LHON gene mutation, there are several impacts on the cell:

  • The cell is much less efficient at releasing usable energy from food.
  • Damaging by-products called ROS (Reactive Oxygen Species) or Free Radicals are formed.
  • Energy is wasted as heat.
  • Cell signals may be triggered by damaged mitochondria, such as Apoptosis, or cell shut-down.
  • The cell may lost the ability to manage its chemical balance, such as the Calcium balance.

Homoplasmy and Heterplasmy

A cell contains many mitochondria, and each one has its copy of the Mitochondrial Chromosome.

HOMOPLASMY is when all of the mitochondria have the same form of a gene, say the LHON G11778A mutation.

If some of the mitochondria in the cell have the G11778A LHON mutation, and the rest have the normal or “wild-type” version of the gen, then scientists call this HETERPLASMY.

When doctors do a blood test for a LHON gene, they will get an indication of the percentage of mitochondria carrying that gene.

So they may say that the test result was “Homoplasmic for G11778A”.  This would mean that all of the mitochondria had the mutated form of the gene.

They may say that the person is Heteroplasmic for the G11778A mutation, with 80% mutation.

That would mean that 8 out of 10 mitochondria have the LHON mutation, and 2 out of 10 have the wild-type version of the gene.

The first diagram represents a cell where all of the mitochondria have the wild-type gene.

Homoplasmic Cell

This diagram represents a cell which is heteroplasmic for the gene.  4 out of 10 mitochondria carry a mutated form of the gene.

Heteroplasmic cell

Some scientists believe that someone who has inherited a LHON gene must have a minimum percentage of affected mitochondria to develop LHON.  See the Threshold Trigger Proposal page.

Weh someone is heteroplasmic for a LHON mutation, their mitochondria might have a mix of affected and unaffected chromosomes.

Retinal Ganglion Cells

 

When someone is affected by LHON, the major symptom is the rapid loss of central vision.

Doctors think that the LHON mutation affects the Retinal Ganglion Cells (RGCs).

Each eye has a focusing system which throws an image of light onto the delicate lining at the back of the eye. This lining is called the Retina.

The Retina is made up of Pigment Epithelium Cells, light sensitive Rods and Cones, the Bipolar layer and the Retinal Ganglion Cells.

The eye still focuses properly and throws a sharp image on the retina.

The Rods and Cones convert the image into electrical nerve impulses and pass them to the connecting layer of Bipolar Cells.

the Bipolar Cells pass the nerve impulses onto the Retinal Ganglion Cells.

RGCs are a kind of nerve cell.  Each RGC has one outgoing arm or Axon. The axons from the RGCs form the Retinal Nerve Fiber Layer of the Retina.

These axons all lead to the Optic Disc and then exit the eyeball on the way to the Brain.

For a simple description of the eye and eyesight look at the page Eyesight 101.

Once the axons or nerve fibers leave the eyeball, they are covered in an insulating layer called Myelin. This insulatinjg layer stops the signals from adjacent axons interfering with eacdh other and drastically lowers the amount of energy needed to send a nerve impulse.

The millions of Retinal Ganglion Cells covering the surface of the Retina each have one long axon running over the Retina in the Retinal Nerve Fiber Layer. These converge on the Optic Nerve head and form the Optic Nerve.  The nerve is not one fiber like a piece of electrical wire, it is made up of a huge number of tiny individual fibers.

 

The RGCs are not all the same size – the ones clustered tightly together in the region called the Macula are smaller than the ones around the edges of the Retina.

Doctors think that the smaller RGCs are more badly affected by the LHON mutations. That explains why the RGCs in the center of the visual field are affected first, and then the problem spreads outwards. (19268652)

Once LHON symptoms start, RGCs go dormant and eventually die.(20943885)(22423654)

Althouth researchers think that the lowered ability to produce ATP fuel causes LHON, they have not yet worked out exactly how.

Understanding the exact way that a LHON mutation causes the damage to Retinal Ganglion Cells would be a major step in understanding why some people are affected and others are not.

The Retinal Ganglionj Cells have a high energy need because the axons forming the Optic Nerve cannot have an insulating myelin sheath inside the eyeball. It takes more energy to transmit a signal from the RGC body to the optic nerve head than it does to transmit a nerve signal along the insulated optic nerve.cite]http://www.ncbi.nlm.nih.gov/pubmed/26126824[/cite]

One possibility is that nerve cells need a lot of ATP to move chemical signals around and transmit them to other nerve c ells. (2467078)

Another possibility is that the LHON affected version of Complex I generates a lot more Reactive Oxygen Species than the unaffected version.  ROS are always produced as the high-energy electrons travel along the Electron Transport Chain, because some of the energetic electrons “leak”” away.  The LHON mutations might cause a lot more ROS.  this means less energy is being used to make ATP Fuel, and parts of the Mitochondria are being damaged by contact with these reactive chemical molecules.

The high levels of ROS trigger a “cell damage” signalling mechanism which leads to something called Apoptosis, or “programmed Cell Death”.  Apoptosis is a mechanism the body uses to get rid of unwanted cells while developing, or to kill of damaged and diseased cells. (24792485)

 

References

Molecular Biology of the Cell 6th edition 

Hereditary Optic Neuropathies Eye (2004) 18, 1144–1160. doi:10.1038/sj.eye.6701591

Leber Hereditary Optic Neuropathy Yu-Wai-Man P, Turnbull D, Chinnery P; BMJ Jornal of Medical Genetics 2002 Mar 39(3) 162-9

NCBI Gene Reviews – LHON

NIH Genetics Home Reference – LHON

This page was last updated September 19 2015

 

 

 

 

 

Bibliography

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