Nature: Mitochondria have a waste disposal mechanism that gets rid of mutated mtDNA

Scientists at the University of Cologne have discovered how cells eliminate mutated mitochondrial DNA (mtDNA).

Mitochondria are the powerhouses
of our cells.
Since they evolved from bacteria, they still have genetic material
wrapped in chromosomal structures (nucleoids).
They convert the chemical energy in food into a biousable form
.
A team of researchers from the Centre of Physiology of the University of Cologne, the Centre for Molecular Medicine Cologne (CMMC) and the CECAD Cluster of Excellence in Aging Research have now shown that mutations in mtDNA lead to local rearrangements
of proteins in the mitochondrial membrane.
The mutated mtDNA is locked, eliminated, and subjected to autophagy, the cell's "waste disposal.
"

In many tissues, mutations in mtDNA are the result of
normal aging.
These types of mutations are an important cause
of many aging-related diseases.
There are thousands of copies of mtDNA in every cell, so mitochondrial function is impaired
only when the percentage of mutated mtDNA molecules exceeds a certain threshold.
It has long been established that mitochondrial damage, including acute mtDNA damage, triggers the process
of mitophagy.
In this process, dysfunctional mitochondrial parts are selectively degraded and recycled
.

Dr.
David Pula-Martin, lead author of the current study, explains the details: "What's new in our study is that this mechanism does not affect the mitochondrial endowment of cells, but only clears damaged mitochondrial DNA
.
By labeling neighboring proteins—so-called proximity markers—we found that damage to mtDNA leads to the aggregation
of endosomes near the nucleoid.
Their removal is coordinated by the interaction of the nucleoid protein Twinkle and the mitochondrial membrane proteins SAMM50 and ATAD3
.
”

"ATAD3 controls their distribution, and SAMM50 induces the release and transfer of nucleoids to so-called endosomes
.
" This also prevents the activation
of the immune response.
"The protein VPS35, a major component of reverse transcriptase, mediates the maturation of early endosomes into late autophagy vesicles, degradation and cycling eventually occur
.
"

By using a mouse model in which mtDNA mutations lead to impaired muscle regeneration, the scientists also showed that selectively mutated mtDNA can be removed
by stimulating the activity of autophagy mechanisms with rapamycin.
Thus, the total number of mtDNA copies remains constant, maintaining mitochondrial function
.

Professor Rudolf Wiesner, head of the research team, added: "Mutations in the genes encoding these proteins can lead to serious neurological diseases such as VPS35, such as Parkinson's disease
.
" We now want to use these proteins as new molecular targets to open up entirely new treatments
for these aging-related diseases.
" "Although there is still a long way to go for therapeutic application, the research team has already seen a promising approach
.
"