Mitochondria produce the cell's major
energy currency: ATP. If mitochondria become dysfunctional, this can be
associated with a variety of devastating diseases, from Parkinson's disease to
cancer. Technological advances have allowed us to generate huge volumes of data
about these diseases. However, it can be a challenge to turn these large,
complicated, datasets into basic understanding of how these diseases work, so
that we can come up with rational treatments.
We were interested in a dataset (see here)
which measured what happened to cells as their mitochondria became
progressively more dysfunctional. A typical cell has roughly 1000 copies of
mitochondrial DNA (mtDNA), which contains information on how to build some of
the most important parts of the machinery responsible for making ATP in your
cells. When mitochondrial DNA becomes mutated, these instructions accumulate
errors, preventing the cell's energy machinery from working properly. Since
your cells each contain about 1000 copies of mitochondrial DNA, it is
interesting to think about what happens to a cell as the fraction of mutated
mitochondrial DNA (called 'heteroplasmy') gradually increases. We used maths to try and explain how a cell
attempts to cope with increasing levels of heteroplasmy, resulting in a wealth
of hypotheses which we hope to explore experimentally in the future.
The central idea arising from our analysis
of this large dataset is that cells seem to attempt to maintain the number of normal
mtDNAs per cell volume as heteroplasmy initially increases from 0% mutant. We
suggest they do this by shrinking their size. By getting smaller, cells are
able to reduce their energy demands as the fraction of mutant mtDNA increases,
allowing them to balance their energy budget and maintain energy supply =
demand. However, cells can only get so small and eventually the cell must
change its strategy. At a critical fraction of mutated mtDNA (h* in the cartoon
above), we suggest that cells switch on an alternative energy production mode
called glycolysis. This causes energy supply to increase, and as a result,
cells grow larger in size again. These ideas, as well as experimental proposals
to test them, are freely available in the Biochemical Journal "Mitochondrial DNA Density Homeostasis Accounts for a Threshold Effect in a Cybrid Model of a Human Mitochondrial Disease". Juvid, Iain and Nick
