Doctoral defence: Akbar Zeb “The novel mechanisms of Parkin-dependent mitophagy”

On 30 March at 14:00 Akbar Zeb will defend his doctoral thesis The novel mechanisms of Parkin-dependent mitophagy”.

Professor Allen Kaasik, University of Tartu
Associate Professor Vinay Choubey, University of Tartu
Associate Professor Džamilja Safiulina, University of Tartu

Professor Michelangelo Campanella, University of London (United Kingdom)

The main aim of this thesis was to unravel novel molecular mechanisms regulating mitophagy, selective removal of damaged mitochondria from the cell.

The data presented here highlight crosstalk between the PINK1-Parkin mitophagy and the KEAP1-NRF2 pathway. PINK1-Parkin mediated mitophagy is the major mitophagy pathway regulated by the mitochondrial kinase protein PINK1 and the E3 ubiquitin ligase Parkin. Both proteins have been linked to the autosomal recessive form of Parkinson’s disease. KEAP1-NRF2 pathway, on the other hand, is the major oxidative stress-response pathway that activates cellular antioxidant defense mechanisms. The pathway is regulated primarily by nuclear erythroid factor-2 (NEF2)-related factor-2 (NRF2) and Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein1 (KEAP1).

The thesis also attempted to define the role of mitochondrial transport protein Miro (mitochondrial rho GTPase) in the regulation of PINK1-Parkin‐mediated mitophagy.  Miro is a mitochondrial outer membrane protein that is required for the transport of mitochondria along the microtubules. It is a well-known substrate of Parkin. Parkin subjects Miro for proteasomal degradation and thereby helps to uncouple damaged organelles from the functional mitochondrial network.

Additionally, the thesis also briefly evaluated the role of mitochondrial biogenesis for neuronal development. To this end, the expression of PGC-1α (peroxisome proliferator-activated receptor gamma coactivator-1α) was examined in axonal growth and mitochondrial density in neurons. PGC-1α is a transcriptional coactivator that plays an important role in mitochondrial biogenesis.

Human, rat, and mice origin cell culture-based in vitro methods were used in this thesis. Briefly, the cells were first grown overnight, then transfected with desired DNA constructs and further incubated, and finally used for data acquisition by using techniques like microscopy imaging, fluorescence/luminescence assays, and western blotting.

The data obtained allow us to propose a mechanism that enables the cell to eliminate damaged mitochondria by enhancing mitophagy. We demonstrate that increased mitochondrial ROS (reactive oxygen species) production disrupts the KEAP1-PGAM5 complex that will block PGAM5 (phosphoglycerate mutase 5) processing.  Accumulation of PGAM5, in turn, will interfere with PINK1 processing leading to the stabilization of mitochondrial PINK1. This will stimulate Parkin translocation to mitochondria, activates mitophagy and leads to the removal of ROS-producing mitochondria. In such a way, enhanced ROS level ensures a negative feedback down-regulating mitochondria, the main source of ROS.

We also identified a new additional step in the initiation of mitophagy by showing that Parkin interacts with mitochondrial Miro proteins prior to the onset of mitochondrial damage. This initial interaction does not involve the ubiquitination of Miro, nor does it require PINK1. Upon damage to mitochondria, this complex of Miro-Parkin activates and leads to the ubiquitination of Miro, enhances Parkin translocation, and subsequent initiation of mitophagy.

Further, the results also briefly show that overexpression of PGC-1α led to an increase in the total number of mitochondria in the axonal tree, suggesting that mitochondrial biogenesis is required for the axonal growth of neurons. 

Knowledge of the mechanisms presented in this thesis might have important medical implications, especially in neurodegenerative diseases (like Alzheimer's and Parkinson's disease) where the accumulation of damaged mitochondria plays a central role. Pharmacological stimulation of the mentioned pathways could allow to activate the weakened mitophagy and thereby eliminate the damaged mitochondria. Further studies are needed to identify whether these mitophagy activators could bolster mitochondrial health and ameliorate cell viability in neurodegenerative pathologies.

The defence will be held in Ravila 19–1006 and in MS Teams.

Andres Tennus

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