When mitochondria become damaged, they avoid causing further problems by
signaling cellular proteins to degrade them. In a paper publishing April 11,
2019, in the journal Developmental Cell, scientists in Norway
report that they have discovered how the cells trigger this process, which is
called mitophagy. In cells with broken mitochondria, two proteins — NIPSNAP 1
and NIPSNAP 2 — accumulate on the mitochondrial surface, functioning as “eat
me” signals, recruiting the cellular machinery that will destroy them.
NIPSNAP 1 and 2 are normally found inside healthy mitochondria, although
their function inside the cell is unknown. “When a cell’s respiration chain is
disrupted, and the mitochondria are damaged, import of these proteins into the
matrix and inner membrane space of the mitochondria is interrupted,” says
senior author Anne Simonsen, a professor at the Department of Molecular
Medicine at the Institute of Basic Medical Sciences of the University of Oslo.
“In that case, the import system does not function and they remain bound to the
surface of the damaged mitochondria signaling for mitophagy.”
In this study, the researchers studied human HeLa cells where both NIPSNAP1
and NIPSNAP 2 function were eliminated. “When we do that, these cells cannot
clear the mitochondria after damage,” says Simonsen. However, in cells with
functional NIPSNAP proteins, when mitophagy was induced through the addition of
a chemical disruptor, they observed that the NIPSNAP proteins act in concert
with the PINK and PARKIN proteins, proteins already known to have a role in
triggering autophagy and to have a role in Parkinson’s Disease.
PARKIN labels cells with ubiquitin, a small protein that directs the cells
towards degradation. “Ubiquitin is the classical signal to recruit autophagy,”
says co-author Terje Johansen (@TerjeJohansen17), of the University of Tromsø —
The Arctic University of Norway. “What we saw is that in addition to ubiquitin,
NIPSNAP proteins are required to recruit autophagy proteins; they are not
targeted to the mitochondria unless these NIPSNAP proteins are found on the
surface.”
The team showed this finding has important physiological implications in
vivo by investigating the NIPSNAP/PINK/PARKIN mechanism in a zebrafish animal
model. They compared wild-type zebrafish and a fish line with reduced NIPSNAP1
protein abundance.
“We see that the mutant fish lacking adequate functional NIPSNAP1 are not
able to move as the wild-type fish,” says Simonsen. They have a
Parkinsonian-like phenotype with reduced numbers of dopaminergic neurons.
However, they could rescue this locomotion defect by adding L-dopa, the same
compound used to treat human Parkinson’s Disease, to the water.
Even more dramatically, animals entirely lacking NIPSNAP1 protein died
within five days. “Clearly, clearance of mitochondria is important for the
health of these dopaminergic neurons. That is particularly important since
neurons generally cannot divide,” says Johansen.
As evolutionarily conserved proteins, NIPSNAP proteins are found throughout
the animal kingdom, including humans.
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