The Mitochondrial Free Radical Theory of Aging

Aubrey de Grey ag24 at mole.bio.cam.ac.uk
Wed Nov 24 18:14:11 EST 1999


Randall Parker wrote:

> Is it a gene that is right in the mtDNA that codes for the machinery that 
> determines the mapping from DNA triplet to amino acid? Something has to 
> attach an amino acid to each tRNA. If that gets mutated then total junk 
> will get transcribed.

The proteins that do this attachment are all nuclear-coded already.  The
mapping from DNA to protein (the genetic code) is not defined in them,
however, but in the tRNAs themselves, which ARE mt-coded.  Thus, this:

> If so, then if the old mtDNA was left around when the new mtDNA was 
> introduced then the old encodings would cause the translation mechanism 
> to still continue to be very wrong.

is still right in the case of mutations which cause incorrect proteins
to be built in the mitochondria (rather than just no proteins).  It
remains to be seen whether such mutations are common enough to warrant
action against this, but is they are then options include elimination
of mtDNA replication or transcription by disrupting the (nuclear) genes
that perform those processes, or else by binding to the mtDNA and
blocking the passage of the polymerases.

> If there are signals that tell a mitochondrion to replicate then couldn't 
> one:
> 
> 1) Inject a gene into all mitochondria that makes a protein that affects 
> a mitochondrion's ability replicate. In particular, make this a protein 
> that can prevent mitochondrial replication.
> 
> 2) Make that protein's synthesis or activation/deactivation be dependent 
> upon chemical signals that will be found in good mitochondria but that 
> typically will not be found in bad mitochonidria.
> 
> The question then becomes can one come up with a set of signals that 
> would be foolproof.

This is very problematic because mitochondria undergo many transient
changes of composition (especially of various ions) which I doubt could
be distinguished from permanent changes due to mutations.

> How many copies of mtDNA are in each mitochondrion?

Five or so.

> I see one approach where if many mtDNAs are present per mitochondrion 
> then insert one extra one that is thoroughly wrapped up in protein.
> This special copy of the mtDNA would perhaps ... 
> be a complex molecule whose sections get used periodically as a golden 
> standard against which other mtDNAs are compared.

The nuclear DNA is indeed wrapped up as you describe, in proteins called
histones.  However, introducing such a drastic change in the environment
of the mtDNA would undoubtedly prevent the action of the normal proteins
involved in its replication and transcription.

Aubrey de Grey





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