Errea 2015 J Neuroinflammation

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Errea O, Moreno B, Gonzalez-Franquesa A, Garcia-Roves PM, Villoslada P (2015) The disruption of mitochondrial axonal transport is an early event in neuroinflammation. J Neuroinflammation 12:152.

Β» PMID: 26310930

Errea O, Moreno B, Gonzalez-Franquesa A, Garcia-Roves PM, Villoslada P (2015) J Neuroinflammation

Abstract: BACKGROUND: In brain inflammatory diseases, axonal damage is one of the most critical steps in the cascade that leads to permanent disability. Thus, identifying the initial events triggered by inflammation or oxidative stress that provoke axonal damage is critical for the development of neuroprotective therapies. Energy depletion due to mitochondrial dysfunction has been postulated as an important step in the damage of axons. This prompted us to study the effects of acute inflammation and oxidative stress on the morphology, transport, and function of mitochondria in axons.

METHODS: Mouse cerebellar slice cultures were challenged with either lipopolysaccharide (LPS) or hydrogen peroxide (H2O2) ex vivo for 24 h. Axonal mitochondrial morphology was evaluated by transmission electron microscopy (TEM) and mitochondrial transportation by time-lapse imaging. In addition, mitochondrial function in the cerebellar slice cultures was analyzed through high-resolution respirometry assays and quantification of adenosine triphosphate (ATP) production.

RESULTS: Both conditions promoted an increase in the size and complexity of axonal mitochondria evident in electron microscopy images, suggesting a compensatory response. Such compensation was reflected at the tissue level as increased respiratory activity of complexes I and IV and as a transient increase in ATP production in response to acute inflammation. Notably, time-lapse microscopy indicated that mitochondrial transport (mean velocity) was severely impaired in axons, increasing the proportion of stationary mitochondria in axons after LPS challenge. Indeed, the two challenges used produced different effects: inflammation mostly reducing retrograde transport and oxidative stress slightly enhancing retrograde transportation.

CONCLUSIONS: Neuroinflammation acutely impairs axonal mitochondrial transportation, which would promote an inappropriate delivery of energy throughout axons and, by this way, contribute to axonal damage. Thus, preserving axonal mitochondrial transport might represent a promising avenue to exploit as a therapeutic target for neuroprotection in brain inflammatory diseases like multiple sclerosis. β€’ Keywords: Mitochondria, Axonal transport, Axonal damage, Inflammation, Oxidative stress, Multiple sclerosis

β€’ O2k-Network Lab: ES Barcelona Garcia-Roves PM, ES Barcelona IDIBAPS Hospital Clinic

Labels: MiParea: Respiration, mt-Medicine  Pathology: Other  Stress:Oxidative stress;RONS  Organism: Mouse  Tissue;cell: Nervous system  Preparation: Homogenate 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, CIV, NS, ROX  HRR: Oxygraph-2k 

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