By Christina Towers, PhD
Mitophagy in the Brain
Selective autophagic degradation of damaged mitochondria, known as mitophagy, has been described as a cyto-protective process. Accordingly, defects in mitophagy have been associated with a number of diseases including muscle atrophy, cancer, and multiple neurodegenerative diseases. Defective mitophagy has been best described in neurons, where the accumulation of damaged mitochondria and the resulting increase in reactive oxygen species (ROS) can contribute to cellular apoptosis and degeneration particularly in diseases like Parkinson's, Alzheimer's, and Huntington's disease.1 Currently, there is a lack of potent and specific pharmacological agents to induce autophagy in the brain; which are necessary tools to study the potentially protective effects of autophagy in these pathologies. To this end, Pasquale D’Acunzo et al created an optogenetic tool to temporally and reversibly induce mitophagy in different cell types including neuronal-derived cells.
Inducing mitophagy with light
In a recent publication in Nature Communications, the authors describe a bimodular system that relies on the rapid and transient dimerization of iLID and sspBmicro after blue light stimulation.2 They N-terminally fused the core autophagy protein, AMBRA1, to the TagRFPt-sspBmicro protein and the mitochondrial outer membrane signal peptide, ActA, to Venus-iLID. In the dark AMBRA1 remains in the cytosol, but after short and intermittent bursts of blue light iLID undergoes a conformational change allowing it to bind with high affinity to sspBmicro forcing AMBRA1 to the mitochondria’s outer membrane. It has been previously shown that forcing AMBRA1 localization to the mitochondria induces mitophagy which is LC3 dependent but independent of both p62 and Parkin. Here, the authors confirmed this finding and showed that light stimulation in this system could induce mitochondrial morphological changes and accumulation of mito-aggresomes.3
Immunohistochemistry: AMBRA1 Antibody [NBP1-07124] - IHC analysis of AMBRA1 in mouse brain using DAB with hematoxylin counterstain.
The authors go on to demonstrate a broad application of the technique and confirm mitophagy induction in human T-lymphocytes as well as in a model organism system: zebra fish. Lastly, as a proof of concept, they use a model of neurotoxicity to show that mitophagy induction after blue light treatments could prevent neurotoxicity in Embryonic Telencephalic NAïve (ETNA) cells, a line derived from murine E14 striatum primordia neurons.
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Significance for understanding the role of mitophagy in disease
This new optogenetic tool will be instrumental in studying the temporal and spatial regulation of mitophagy and its role in preventing neurotoxicity. For example, it would be most interesting to microinject Venus-iLID-ActA/AMBRA1- RFP-sspB expressing plasmids into zebra fish models of Alzheimer’s disease or cancer to better understand when during disease progression mitophagy induction might be most effective. Researchers could also use this tool to spatially control mitophagy induction by focusing blue light on specific cell populations elucidating in which cell type mitophagy is most critical. While there are still many unanswered questions in the field of autophagy and specifically mitophagy, this new optogenetic tool may provide a necessary leap forward in understanding the basic cell biology behind these important processes.
Christina Towers, PhD
University of Colorado (AMC)
Dr. Towers studies the roles of autophagy, apoptosis and cell death in cancer.
- Towers, C. G., & Thorburn, A. (2016). Therapeutic Targeting of Autophagy. EBioMedicine. https://doi.org/10.1016/j.ebiom.2016.10.034
- D'Acunzo, P., Strappazzon, F., Caruana, I., Meneghetti, G., Di Rita, A., Simula, L., … Cecconi, F. (2019). Reversible induction of mitophagy by an optogenetic bimodular system. Nature Communications. https://doi.org/10.1038/s41467-019-09487-1
- Strappazzon, F., Nazio, F., Corrado, M., Cianfanelli, V., Romagnoli, A., Fimia, G. M., … Cecconi, F. (2015). AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death and Differentiation. https://doi.org/10.1038/cdd.2014.139