A retrograde transit filter mediated by optineurin controls mitostasis in distal axons

Marahori, N. A.; Gailer, B.; Schifferer, M.; Kleele, T.; Iatroudi, A.; Hannan, S. B.; Avramopoulos, P.; Engelhardt, S.; Lakadamyali, M.; Brill, M. S.; Misgeld, T.

doi:10.1101/2024.07.28.604753

bioRxiv · 10.1101/2024.07.28.604753

A retrograde transit filter mediated by optineurin controls mitostasis in distal axons

Marahori, N. A.·Gailer, B.·Schifferer, M.·Kleele, T.·Iatroudi, A.·Hannan, S. B.·Avramopoulos, P.·Engelhardt, S.·Lakadamyali, M.·Brill, M. S.·Misgeld, T.

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Abstract

The mechanisms of mitochondrial homeostasis in neurons-- mitostasis--are enigmatic and disease-prone, given a neurons large synaptic pool of mitochondria. To better understand mitostasis in mature mouse motor axons, we used ex vivo optical pulse-chase measurements of mitochondrial volume flux and identified a reiterative degradation system near presynaptic terminals and distal paranodes, which accounts for 75% of mitochondrial turnover in synapses. This distal filter system captures dysfunctional mitochondria from the retrograde stream and redirects them for lysosomal degradation. It depends on optineurin, a motor neuron disease-related mitophagy adaptor, but not on PINK1 and parkin, implicating a non-canonical mitophagy pathway. In presymptomatic motor neuron disease models, where retrograde transport is disrupted, the fraction of removed mitochondria is increased. Thus, we identify a new mitostasis system in distal axons with a cascade of checkpoints for local mitophagy, which normally maintains mitochondrial mass balance but is disrupted early in degenerative axonopathies.

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Marahori, N. A., Gailer, B., Schifferer, M., Kleele, T., Iatroudi, A., Hannan, S. B., Avramopoulos, P., Engelhardt, S., Lakadamyali, M., Brill, M. S., Misgeld, T.. 2024-07-29. A retrograde transit filter mediated by optineurin controls mitostasis in distal axons. https://doi.org/10.1101/2024.07.28.604753

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