All tags Metabolism The link between transmitophagy and cognitive diseases: MitoNews, volume 10, issue 2

The link between transmitophagy and cognitive diseases: MitoNews, volume 10, issue 2

Transmitophagy: mitochondria go ‘green’.

Edited by James Murray, PhD.

Thousands of researchers around the world are studying the connections between mitochondria, metabolism and disease. MitoNews summarizes a selection of the latest published findings and highlights how Abcam's MitoSciences Range of research tools has contributed to this effort.

Read the full list of 144 original research papers published in recent months.

In MitoNews we have previously reported work in the area of autophagy.  Autophagy (“to self-eat”) can be likened to cellular trash collection, or perhaps recycling is a more appropriate term, where proteins are degraded and building blocks are ‘recycled’ for bio- synthesis. 

This process, when referring to mitochondria, is sometimes termed mitophagy.  Whether autophagy or mitophagy, the process has been considered, to this point, an entirely internalized cellular process – i.e. a healthy cell degrades its own mitochondria. 

However in recent work, featured on the cover issue of the July 1st 2014 edition of PNAS, Davis et al., show that retinal ganglion cells of normal mice can export damaged mitochondria to their neighboring astrocytes at the optic nerve head (ONH). 

This is the first observation of its kind, gives rise to the term transmitophagy, and prompts us to re-evaluate our assumptions about this cellular pathway.

Intact and degraded mitochondria were identified in axonal evulsions at contact sites with neighboring astrocytes by high-resolution transmission electron microscopy in 3 and 9 month old mice retinas. 

A tandem transgene, encoding fluorescent acid-sensitive-EGFP and fluorescent  acid-insensitive-mCherry targeted to mitochondria, was introduced by intravitreal injection.  Expression was detected in the retinal ganglion cell layer (GCL) where fluorescence accumulated in mitochondria as shown by co-localization of both fusion proteins and ATP synthase alpha subunit in a mitochondrial pattern. 

Fluorescent protein encoding mRNA transcripts were enriched in cells also expressing the retinal ganglion marker gamma synuclein, but not in cells expressing the astrocyte marker vimentin.  This indicates that the intravitreal injection induces expression of the fluorescent reporter gene in the retinal cell layer but not further into the astrocytes of the optical neural head. 

Despite the lack of reporter mRNA in astrocytes, a fluorescent signal from the acid-insenstive-mCherry protein, but not signal from the acid sensitive EGFP, was seen in the astrocyte cells.  This fluorescent signal was detected in discrete puncta and co-localized with both a classical marker of acidic lysosomes, LAMP1 ( lysosomal-associated membrane protein 1), and an astrocyte marker, Mac2. 

These findings indicate that mitochondria from the retinal ganglion, containing the fluorescent mitoEGFP-mCherry reporter protein, are exported and degraded in lysosomes of the neighboring astrocytes.  Statistical image analysis indicates that this is not a limited process, in fact astrocytes probably degrade a large proportion of retinal ganglion cell mitochondria by this process of transcellular degradation of mitochondria, or transmitophagy. 

It is unknown whether these damaged mitochondria are transported from within the main ganglion cell body, the soma, along the length of the axon to the region bordering the astrocyte, or whether they are simply local mitochondria and it is energetically more favorable, or safer, to degrade them in a proximal, perhaps specialized, phagocytic astrocyte. 

Accumulation of damaged cellular components, and in particular damaged mitochondria, have been implicated in numerous diseases.  Impairments in bioenergetic functioning and trafficking along the length of neuronal axons may be causative in neurological disorders such as Parkinson’s and Alzheimer’s disease. 

Transmitophagy may be a widespread process in neurons to mitigate the risk of axonal accumulation of damaged proteins and mitochondria, and one, which gone awry, may result in neurological disease. 

Transcellular degradation of axonal mitochondriaProc Natl Acad Sci 2014.  Davis C.H., Kim K.Y., Bushong E.A., Mills E.A., Boassa D., Shih T., Kinebuchi M., Phan S., Zhou Y., Bihlmeyer N.A., Nguyen J.V., Jin Y., Ellisman M.H., Marsh-Armstrong N.

References

Bulk autophagy, but not mitophagy, is increased in cellular model of mitochondrial disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2014. Moran M., et al.

Optic atrophy 1 mediates mitochondria remodeling and dopaminergic neurodegeneration linked to complex I deficiency. Cell Death and Differentiation, 2013. Ramonet D., et al.

Quantitative Proteomics of Synaptic and Nonsynaptic Mitochondria: Insights for Synaptic Mitochondrial VulnerabilityJ. Proteome Res, 2014. Stauch K.L., et al.

PINK1-Parkin Pathway Activity Is Regulated by Degradation of PINK1 in the Mitochondrial Matrix. PLOS Genetics, 2014. Thomas R.E., et al.

Aging synaptic mitochondria exhibit dynamic proteomic changes while maintaining bioenergetic functionJ Aging 2014. Stauch K.L., et al.

Astrocyte-dependent protective effect of quetiapine on GABAergic neuron is associated with the prevention of anxiety-like behaviors in aging mice after long-term treatment. J Neurochemistry, 2014. Wang J., et al.

Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer's disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2014. Pedros I., et al.

MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife, 2014. Yun J., et al.

Mitochondria hyperfusion and elevated autophagic activity are key mechanisms for cellular bioenergetic preservation in centenarians. J Aging 2014. Sgarbi G., et al.

Msp1/ATAD1 maintains mitochondrial function by facilitating the degradation of mislocalized tail-anchored proteins. The EMBO Journal, 2014. Chen Y.C., et al.

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