.. A Guide to the Genetics of .. 


                    .. Leber's Hereditary Optic Neuropathy 'LHON' ..


                              .. a Mitochondrial Disorder of the Enzyme 'Complex I' ..






      A hypothesis to explain some of the features of LHON ..


This diagram comes from a recent paper by Drose(2011) and, in my opinion, gives

some real clues to the understanding of the enigmatic features of LHON.


    proton pump jpg


The diagram shows that the enzyme COMPLEX I has 2 proton pumps situated side by side,

with one pump labelled PP, for Proximal Pump, and the other labelled DP, for Distal Pump.


The PP contains the the mitochondrial peptides MT-ND1, MT-ND2, MT-ND3, MT-ND4L and MT-ND6, with a number of subunits.

whilst the DP contains the mitochondrial peptides MT-ND4 and MT-ND5, again with some subunits.


So, in a person with a LHON mutation, G3460A & T14484C will be found in the PP and G11778A in the DP.



BUT ... can this description of COMPLEX I having 2 proton pumps be used to explain some of the features of LHON ?


First, consider the following diagram which explains how the function of the 2 proton pumps

might be altered by the presence of a LHON mutation.


     pump function jpg



where .... in case (a) - normal mtDNA allows for 100% of Proton pumping power to come from the 2 pumps working correctly,

but ...... in case (b) - in the presence of a LHON mutation such as G3460A or T14484C the DP has little, or no, function, 

and ...... in case (c) - in the presence of a LHON mutation such as G11778A the PP has little, or no, function,

Finally .. in case (d) - in the presence of a 'poison', perhaps Methanol, or Rotenone, there is very little, if any, function.



So let us see how this might work:

Consider that in a 'Population of Normal People' the ability to manufacture Complex I
might be much higher that the amount actually needed by cells most of the time.

Perhaps 'normal' cells with  their 2 pumps working might be able to manufacture twice as much Complex I as ever needed. 

      Figure1


However, a LHON mutation leaves the cell with 1 pump working,
and in this situation, if 'supply' is exceeded by the 'need' for Complex I LHON disease may occur.

      Figure2



THE 'DEMAND' & 'SUPPLY' PROBLEM in respect of COMPLEX I


The last diagram suggests that the 'DEMAND' for the manufacture of Complex I is fairly constant,
varying in amount in a normal distribution. It is not clear as what factors might alter the 'DEMAND'
in a cell, or indeed a single mitochondrion, but it is feasible that an excess of ADP stimulates
'DEMAND' and this leads to mitochondrial fission, growth and the assembly of more Complex I units. 

And .. in turn a low level of ADP would decrease the 'DEMAND' on the system; allowing for the cell 

The result of the 'DEMAND' rising may be that there is a 'lag'   





Q & A.


The following are some questions about the enigmatic behaviour of LHON
and each question is followed by an answer given using the above hypothesis.



1.  Is LHON caused by mtDNA mutations, such as G3460A, G11778A & T14484C ?

-   Yes, LHON mutations, and mutations in the other subunits, do cause the condition.


2.  Is there is a demonstrable 'fault' associated with the mtDNA mutations ?

-   Yes, a LHON mutation reduces the effectiveness of the enzyme Complex I by 50%.
 

3.  Why does LHON have varying 'penetration', that is some people get symptoms whilst other do not ?

-   The '2 proton pump system' means that if '1 proton pump' should be ineffective the other pump

    can provide 50% of proton pump function; and this may well prove sufficient throughout life.
 

4.  Why do the symptoms and signs of the condition appear suddenly ?

-   The hypothesis does not answer this point - but in as system running at 50% power it is reasonable to consider
    the system is fragile and unable to handle stress, and at such a time there would be sudden failure.  


5.  Is the condition progressive, i.e. after the initial symptoms and signs have stabilised,
    is deterioration to be expected ?

-   The hypothesis answers this well, insofar there is always 50% functioning of the proton pump system
    and this level is perfectly good for life, but not for the proper functioning of the optic nerves.

 
6.  Why do males show more signs of the condition than females ? 

-   The hypothesis does not answer this directly and several possibilities can be considered, so maybe:
  
    .. the double-X in a female makes for greater stability in complex I.
    .. oestrogens in themselves may enhance mitochondrial function
    .. and possibly males are more exposed to toxins, both voluntarily and involuntarily.   

So, overall, it appears that the '2 proton pump system' does explain many of the features of LHON.