Abstract:
Macroautophagy (herein autophagy) is a major intracellular pathway that is
indispensable for maintaining cellular homeostasis. Autophagy has been reported in
various organisms ranging from yeast to humans suggesting that it is an evolutionarily
conserved process. This process was first reported by Christian de Duve (Deter et al.,
1967). He identified this process of self-cannibalization which involves sequestration
of cellular components within a double membranous structure called the
autophagosome, which then fuses with the lysosomes and releases the cargo into it for
degradation. The degradation products, like amino acids are recycled back to the
cytoplasm and are used up by the cell (Klionsky, 2007; Rabinowitz & White, 2010).
This entire phenomenon of cargo capture and ultimately its degradation in the
lysosomes is called ‘autophagic flux’. Basal levels of autophagy occur in all cells during nutrient rich conditions and help in
housekeeping functions (Mizushima et al., 2004; Musiwaro et al., 2013). However,
levels of autophagy dramatically increase via extracellular or intracellular stimulation
such as starvation, pathogen invasion, organelle damage and protein aggregation in
cytoplasm. Thus autophagy can serve as an adaptive response to provide energy and
nutrients to the cell during starvation conditions (Takeshige et al., 1992; Tsukada &
Ohsumi, 1993) and also get rid of aggregated proteins, unnecessary or damaged
organelles and intracellular pathogens (xenophagy) to act as a cellular rubbish
disposal mechanism. Because autophagy is central to maintaining cellular
homeostasis, dysfunctional autophagy has been attributed to a variety of disease
conditions such as cardiovascular diseases, atherosclerosis, certain myopathies, innate
and adaptive immune responses and cancer (Kroemer, 2015). Autophagy also serves a
neuroprotective role, as it clears large aggregates of proteins that are resistant to
proteasomal degradation. Aim and scope of the study
Although the core autophagy machinery and the proteins involved in disease
conditions might be known, but the exact mechanism of action and how the
autophagic flux is regulated is not completely understood which leads to many
unanswered questions. Understanding and controlling the autophagic flux either
through a genetic or pharmacological approach is a highly promising approach and of
great scientific interest. Studies with genetic modulations of autophagic flux have
been carried out in the past with immense success. Yoshinori Ohsumi was awarded
the Nobel Prize in 2016 as a pioneer in the field and his contribution to the study of
autophagic flux. In the present study however, we used the pharmacological approach
as a means to study autophagy. Chemical modulation has an advantage over genetic
manipulations that the phenotype could be observed just on the addition of the
compound and the action could be reversed on its withdrawal. The method is less
laborious and the putative modulators could be used as leads for pharmacological
purposes in certain disease conditions.