Alterations of mitochondrial dynamics allow retrograde propagation of locally initiated axonal insults

Abstract

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.

HSPA9/Mortalin Mediates Axo-Protection by Modulating Mitochondrial Dynamics in Neurons

“…This observation is in line with the recent correlation between Mortalin up-regulation and inhibition of Fis1, a Drp1 mitochondrial receptor, upon antioxidant treatment of hepatocytes (Liu et al, 2017). Our data also further document the fundamental importance of mitochondrial dynamics in axons at the early stages of neurodegeneration (Annweiler et al, 2014;Kim et al, 2015;Lassus et al, 2016;Magnifico et al, 2013;Szelechowski et al, 2014). It should, however, be reminded that mitochondrial dynamics is also required for essential processes regulating cellular physiology, particularly in neurons, such as mitochondrial transport or quality control through mitophagy, as well as synaptic activity.…”

“…Mitochondrial dysfunction and oxidative stress occur early and distally in the pathological process of neurodegeneration. We previously showed that mitochondrial physiology strongly gates axonal vulnerability towards direct axonal insults and that high doses of rotenone are needed to trigger direct axonal degeneration (Lassus et al 2016). Thus, we addressed the influence of Mortalin expression on axonal integrity and sensitivity to oxidative stress, using rat primary cortical neurons grown in microfluidic devices and transduced with LV-Mort, LV-shMortalin or LV-shScr.…”

“…Indeed, axons and somas react very differently to stress, and axons have higher protective signaling capacities than neuronal cell bodies. Insights have been brought by the analysis of Wallerian degeneration (Babetto et al, 2010;Coleman and Freeman, 2010), which enlightened the central role of mitochondria and mitochondrial dynamics in the synaptic and axonal dysfunctions that mark the initiation of neurodegeneration (Cheng et al, 2010;Lassus et al, 2016;Magnifico et al, 2013). Moreover, we recently established a strong association between mitochondrial fragmentation, axonal vulnerability and retrograde spreading of degenerative processes (Lassus et al, 2016).…”

“…We first observed that mitochondrial stress induces down-regulation of Mortalin in primary cultures of cortical neurons. To assess the impact of the variation of Mortalin levels on axonal susceptibility to mitochondrial stress, we used oriented neuronal cultures grown in microfluidic-based devices, which allow a physical separation of axons from their cell bodies and we mimicked the first steps of neurodegeneration by inducing a distal oxidative stress (Lassus et al, 2016;Magnifico et al, 2013;Szelechowski et al, 2014). We used lentiviral vectors to modulate Mortalin levels and we analyzed the impact on mitochondrial morphology, dynamics and sensitivity to distal oxidative stress.…”

Review of nanotheranostics for molecular mechanisms underlying psychiatric disorders and commensurate nanotherapeutics for neuropsychiatry: The mind knockout

“…Psychiatric disorders (neurodegenerative diseases) occur after a series of intriguing incidences such as inflammatory dysfunctions and increased neuroinflammation (peripheral and central nervous system) 1 . These factors collectively activate microglia cells (immune and structural cells) to induce the release of pro-inflammatory cytokines interleukin (IL) -1β, (IL) -18, and tumor necrosis factor-alpha (TNF) -α, that initiates neuronal damages and trigger neuron death 2 . These cells further released fragmented and dysfunctional mitochondria into the brain tissue milieu.…”