Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults.
In chronic neurodegenerative syndromes, neurons progressively die through a generalized retraction pattern triggering retrograde axonal degeneration toward the cell bodies, which molecular mechanisms remain elusive. Recent observations suggest that direct activation of pro-apoptotic signaling in axons triggers local degenerative events associated with early alteration of axonal mitochondrial dynamics. This raises the question of the role of mitochondrial dynamics on both axonal vulnerability stress and their implication in the spreading of damages toward unchallenged parts of the neuron. Here, using microfluidic chambers, we assessed the consequences of interfering with OPA1 and DRP1 proteins on axonal degeneration induced by local application of rotenone. We found that pharmacological inhibition of mitochondrial fission prevented axonal damage induced by rotenone, in low glucose conditions. While alteration of mitochondrial dynamics per se did not lead to spontaneous axonal degeneration, it dramatically enhanced axonal vulnerability to rotenone, which had no effect in normal glucose conditions, and promoted retrograde spreading of axonal degeneration toward the cell body. Altogether, our results suggest a mitochondrial priming effect in axons as a key process of axonal degeneration. In the context of neurodegenerative diseases, like Parkinson's and Alzheimer's, mitochondria fragmentation could hasten neuronal death and initiate spatial dispersion of locally induced degenerative events.
CNRS UMR 8256, Biological Adaptation and Ageing, Paris, 75005, France.|Sorbonne Universités, UPMC, Institut de Biologie Paris-Seine, Paris, 75005, France.
Benjamin
B
Lassus
CNRS UMR 8256, Biological Adaptation and Ageing, Paris, 75005, France.|Sorbonne Universités, UPMC, Institut de Biologie Paris-Seine, Paris, 75005, France.
Sebastien
S
Magnifico
CNRS UMR 8256, Biological Adaptation and Ageing, Paris, 75005, France.|Sorbonne Universités, UPMC, Institut de Biologie Paris-Seine, Paris, 75005, France.
Sandra
S
Pignon
CNRS UMR 5169 Research Center on Animal Cognition, Center for Integrative Biology, Toulouse University, Université Toulouse 3 Paul Sabatier, 31400, France.
Pascale
P
Belenguer
CNRS UMR 5169 Research Center on Animal Cognition, Center for Integrative Biology, Toulouse University, Université Toulouse 3 Paul Sabatier, 31400, France.
Marie-Christine
MC
Miquel
CNRS UMR 8256, Biological Adaptation and Ageing, Paris, 75005, France.|Sorbonne Universités, UPMC, Institut de Biologie Paris-Seine, Paris, 75005, France.
Jean-Michel
JM
Peyrin
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D034281:Dynamins / Q000235:genetics / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D056656:Lab-On-A-Chip Devices; D051379:Mice; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009410:Nerve Degeneration / Q000473:pathology; D052999:Quinazolinones / Q000494:pharmacology; D012402:Rotenone / Q000494:pharmacology
C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; D052999:Quinazolinones; D012402:Rotenone; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse; C486391:Dnm1l protein, mouse; D034281:Dynamins