Molecular Signals of PINK1-Parkindependent MitophagyVandana Bisoyi, Naresh Babu V. SepuriDepartment of Biochemistry, School of Life Sciences,University of Hyderabad, Gachibowli, Hyderabad- 500046 AbstractMitochondria is the major source of ATP production, necessaryfor cellular functions and integrity. Accumulation of mutations in mtDNA canlead to cellular dysfunction by altering oxidative phosphorylation,Ca2+ homeostasis,oxidative stress and protein turnover. Dysfunctionof mitochondria leads to many neuro-degenerative diseases such as Parkinson’sdisease and Alzheimer’s disease.
Hence, damaged mitochondria needs to beeliminated by inducing a plethora of stress signals causing programmed celldeath. Mitochondrial homeostasis and quality control is maintained by a selectiveform of autophagy, i.e., mitophagy.
Earlier studies have shown that multistepsignalling events of PINK1 (PTEN-induced putative kinase1) and Parkin E3Ubiquitin ligase regulates mammalian mitophagy. Here, we review the complexsignal transduction mechanism of PINK1 and Parkin focusing on pathways thatsequester mitochondria to autophagosome. Also post-translational modification suchas ubiquitinylation and phosphorylation of Ubiquitin and Parkin has added abroader perspective to the understanding of cellular damage.Keywords: Mitophagy, PINK1, Parkin, UbiquitinylationIntroductionMitochondriaare organelles enclosed within a double membrane, which is comprised of theouter mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM)(Fig. 1a). Ample amount of mitochondria are present in most cell types whichoccupies proximately 10–40 % of total cellular volume 1. The mitochondrialspace between the OMM and IMM is attributed as the intermembrane space (IMS). Mitochondriaare crucial for eukaryotic cells, as it performs a number of critical functions.
It plays a pivotal role in generation of cellular energy, regulating lipidmetabolism, cytosolic calcium flux buffering and sequestering the cell deathmachinery. Malfunction of the mechanisms that regulate mitochondrial qualitycontrol have proven to be a major driving force of normal ageing 2.Furthermore, failure of mitochondrial quality control mechanisms, causingelevated oxidative stress, is strongly linked to age-related conditions such asneurodegeneration 3, 4.Mostof the cellular chemical energy is produced in the mitochondrial matrix via theprocess of oxidative phosphorylation (OXPHOS), in the form of adenosinetriphosphate (ATP). It involves the oxidation of tricarboxylicacid (TCA) cycle component, acetyl-CoA togenerate NADH and FADH2, which transfer electrons to the electron transportchain components in the inner mitochondrial membrane, terminating in thereduction of oxygen in the matrix to produce an electrochemical gradient acrossthe inner mitochondrial membrane that is used to produce ATP 5. Eventually, electrons are transferred to molecularoxygen (O2), reducing it to H2O (fig). However, due to leakage of electrons at complex I or complex III of theelectron transport chain, O2 can be incompletely reduced which leadsto generation the superoxide anion, the precursor to most Reactive oxygenspecies 6. Low levels of deleterious side-product, ROS plays variousphysiological roles, while high and/or prolonged elevations of ROS can causeoxidation of proteins, lipids, and nucleic acids, leading to cellular dysfunctionand programmed cell death 7.
To combat high levels of ROS, there arenumerous check points to protect the overall integrity of the mitochondrialnetwork. First, mitochondria contains plenty of anti-oxidants such assuperoxide dismutase and glutathione to prevent ROS-induced damage. Secondly,there is a broad collection of cellular factors that repair or replace damagedmitochondrial components.
These factors include mitochondrial chaperones, mitochondrialproteases, DNA repair enzymes and the ubiquitin-proteasomal degradation system.Lastly, when mitochondrial damage becomes too extensive beyond repair, theentire mitochondrion can be selectively degraded in the lysosome through aprocess referred to as mitophagy. MitophagyMitophagy is the selective degradation of defectiveor dysfunctional mitochondria by autophagy. Mitophagy keeps thecell healthy by preventing the accumulation of dysfunctional mitochondria whichcan lead to cellular degeneration. Mitophagy in yeast is mediated by Atg32 and inmammals it is mediated by PINK1 and Parkin mediated pathway as well asindependent pathway. PINK1-Parkin independentpathway involves NIX and its regulator BNIP3. Besides selective removal of damaged mitochondria,mitophagy plays a crucial role in adjustingmitochondrial numbers to changing cellular metabolic needs, and during specificcellular developmental stages, such as during cellular differentiation of red blood cells 8.