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Molecular Signals of PINK1-Parkin
dependent Mitophagy

Vandana Bisoyi, Naresh Babu V. Sepuri

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Department of Biochemistry, School of Life Sciences,
University of Hyderabad, Gachibowli, Hyderabad- 500046

 

Abstract

Mitochondria is the major source of ATP production, necessary
for cellular functions and integrity. Accumulation of mutations in mtDNA can
lead to cellular dysfunction by altering oxidative phosphorylation,
Ca2+ homeostasis,
oxidative stress and protein turnover. Dysfunction
of mitochondria leads to many neuro-degenerative diseases such as Parkinson’s
disease and Alzheimer’s disease. Hence, damaged mitochondria needs to be
eliminated by inducing a plethora of stress signals causing programmed cell
death. Mitochondrial homeostasis and quality control is maintained by a selective
form of autophagy, i.e., mitophagy. Earlier studies have shown that multistep
signalling events of PINK1 (PTEN-induced putative kinase1) and Parkin E3
Ubiquitin ligase regulates mammalian mitophagy. Here, we review the complex
signal transduction mechanism of PINK1 and Parkin focusing on pathways that
sequester mitochondria to autophagosome. Also post-translational modification such
as ubiquitinylation and phosphorylation of Ubiquitin and Parkin has added a
broader perspective to the understanding of cellular damage.

Keywords: Mitophagy, PINK1, Parkin, Ubiquitinylation

Introduction

Mitochondria
are organelles enclosed within a double membrane, which is comprised of the
outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM)
(Fig. 1a). Ample amount of mitochondria are present in most cell types which
occupies proximately 10–40 % of total cellular volume 1. The mitochondrial
space between the OMM and IMM is attributed as the intermembrane space (IMS). Mitochondria
are crucial for eukaryotic cells, as it performs a number of critical functions.
It plays a pivotal role in generation of cellular energy, regulating lipid
metabolism, cytosolic calcium flux buffering and sequestering the cell death
machinery. Malfunction of the mechanisms that regulate mitochondrial quality
control have proven to be a major driving force of normal ageing 2.
Furthermore, failure of mitochondrial quality control mechanisms, causing
elevated oxidative stress, is strongly linked to age-related conditions such as
neurodegeneration 3, 4.

Most
of the cellular chemical energy is produced in the mitochondrial matrix via the
process of oxidative phosphorylation (OXPHOS), in the form of adenosine
triphosphate (ATP). It involves the oxidation of tricarboxylic
acid (TCA) cycle component, acetyl-CoA to
generate NADH and FADH2, which transfer electrons to the electron transport
chain components in the inner mitochondrial membrane, terminating in the
reduction of oxygen in the matrix to produce an electrochemical gradient across
the inner mitochondrial membrane that is used to produce ATP 5. Eventually, electrons are transferred to molecular
oxygen (O2), reducing it to H2O (fig). However, due to leakage of electrons at complex I or complex III of the
electron transport chain, O2 can be incompletely reduced which leads
to generation the superoxide anion, the precursor to most Reactive oxygen
species 6. Low levels of deleterious side-product, ROS plays various
physiological roles, while high and/or prolonged elevations of ROS can cause
oxidation of proteins, lipids, and nucleic acids, leading to cellular dysfunction
and programmed cell death 7. To combat high levels of ROS, there are
numerous check points to protect the overall integrity of the mitochondrial
network. First, mitochondria contains plenty of anti-oxidants such as
superoxide dismutase and glutathione to prevent ROS-induced damage. Secondly,
there is a broad collection of cellular factors that repair or replace damaged
mitochondrial components. These factors include mitochondrial chaperones, mitochondrial
proteases, DNA repair enzymes and the ubiquitin-proteasomal degradation system.
Lastly, when mitochondrial damage becomes too extensive beyond repair, the
entire mitochondrion can be selectively degraded in the lysosome through a
process referred to as mitophagy.

 

Mitophagy

Mitophagy is the selective degradation of defective
or dysfunctional mitochondria by autophagy. Mitophagy keeps the
cell healthy by preventing the accumulation of dysfunctional mitochondria which
can lead to cellular degeneration. Mitophagy in yeast is mediated by Atg32 and in
mammals it is mediated by PINK1 and Parkin mediated pathway as well as
independent pathway. PINK1-Parkin independent
pathway involves NIX and its regulator BNIP3. Besides selective removal of damaged mitochondria,
mitophagy  plays a crucial role in adjusting
mitochondrial numbers to changing cellular metabolic needs, and during specific
cellular developmental stages, such as during cellular differentiation of red blood cells 8.

 

 

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