RL: We're always accustomed to thinking of inheritance as what
happens in terms of the nuclear genome that we
inherit from our mother and the nuclear genome that we inherit from our father.
But what you will see is that, with mitochondria, the particular complement
that is inherited from your mother can be quite different depending
on the egg that is fertilized.
So if we have a primordial egg cell and here we
have the nucleus of the egg cell, this particular egg may have,
let's say, three mitochondria in pink that
carry some sort of defect in their mitochondrial genomes.
And then it may have, let's say, the equivalent
of six mitochondria that are perfectly healthy.
What happens that, is in the process, of differentiation,
of maturation of the eggs, when this undergoes cell division
and you end up with, let's say, two eggs,
you can have a situation where you have a distribution of mitochondria where,
in this case, the cell on the right only received
one of the diseased mitochondria while the cell on the left
actually received two.
What this means is that the quantity, the relative ratio
of normal to defective mitochondria is quite different
if you compare these two egg cells.
So what this means is that, depending on which one is fertilized,
the resulting embryo may have either a significantly greater number
of diseased mitochondria or defective mitochondria versus less.
And so this actually helps determine whether or not the individual in
question-- the resulting child that is produced from that egg--
whether or not that child will express the disease or not express the disease.
Or if it does express the disease, how severely affected
they might be by the mitochondrial disease.
So what this means is that mitochondria and their distribution,
their ratio in a particular egg cell in one woman can be quite variable.
And depending on what egg is fertilized and, thus, what embryo is then
developed, you have a chance that you can have a defect
or you might not have a defect at all.
With mitochondrially-inherited diseases, there is, in fact,
a threshold of defects that can occur-- that you have the inheritance of far
more than just two or three mitochondria,
you have the inheritance of several mitochondria.
And what we can see now are situations in which, let's say, you
have three different eggs.
And I'm not going to show the nuclear DNA because that's not
what we're interested right now.
You might have one egg that has three of the mitochondria that
have the defect, so in pink.
Another one just has one, and another one has two.
Let's say, for the sake of simplicity, all of the other mitochondria,
I will use one color to denote them.
Let's do purple.
So here, we have another three.
Another three.
And let's, for the sake of argument, have another three.
Now, if you compare these three different eggs, what you'll see
is that, in this case, 50% of the mitochondria that that egg has
are defective.
Right?
In this case, we're down to 25% are defective.
One pink to three purple.
And in this case, we see that 40% are defective.
What is observed is that typically, with many mitochondrial diseases,
if you're in the range of 25% to 40% being defective,
you still have enough normal mitochondria to generate enough ATP.
So quite often, these individuals are normal or healthy.
In this case, what we might have is a situation where
50%-- or in fact, what's often the case, 50% to 60%
of mitochondria having the defect can often result in a disease presentation.
So what this means is that you can have siblings in the same family.
You might have one sibling where the egg that was fertilized
had 25% of the mitochondria carrying the defect while another egg was fertilized
for a different sibling that had 50% or more.
This individual up here will show the disease phenotype
while this individual will be entirely healthy.
And so this is one of the remarkable observations with mitochondrial disease
is that, even within the same family, even with siblings, you
can see variations in whether or not the disease is seen, is presented
or not so that one way of thinking about it
is that there is a threshold, if you will,
of the mitochondrial mutation that must be present for the disease
to display itself.
So that, interestingly enough, you may not have realized this,
but for every egg that is fertilized, it's
a little bit of sort of a one-arm bandit where
you pull the lever, three things come up, and, in some cases,
unfortunately, if three defects come up or a high enough percentage
of mitochondria are defective, you cross the threshold for disease.
So this is a very different way of thinking
about how disease might be inherited not through the nuclear genome
but through the mitochondrial genome.
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