Autophagy / Department of Pathological Physiology1
Autophagy
The role in health and disease.
Jan Balvan Ph.D.
Autophagy / Department of Pathological Physiology2
What is Autophagy?
Autophagy is a highly conserved catabolic process induced
under various conditions of cellular stress, which prevents cell
damage and promotes survival in the event of energy or nutrient
shortage and responds to various cytotoxic insults.
Chemical or genetic disturbance of autophagy and the agedependent
decline in autophagic activity have been implicated in
the progression of cancer, neurodegeneration and immune
diseases, as well as ageing.
The most characterized trigger for induction of autophagy is
deprivation of amino acids, which results in inhibition of the
master cell growth regulator serine/threonine kinase mTOR.
Autophagy / Department of Pathological Physiology3
Mechanism of autophagy
Autophagy (from the Greek words auto, meaning ‘self’, and phagein, meaning ‘to eat’) is a fundamental
cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids
and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development
and survival.
Autophagy / Department of Pathological Physiology4
Mechanism of autophagy
Autophagy / Department of Pathological Physiology5
Types of Autophagy
Chaperone-mediated autophagy requires the lysosome-associated membrane protein 2A (LAMP2A), in addition to
molecular chaperones.
Autophagy process can be
distinguished according to how
cargo enters the lysosome
compartment.
In macroautophagy, a doublemembrane
isolation membrane
elongates, expands, and seals to
make an autophagosome around
cytoplasmic components before
fusing with the lysosome.
Microautophagy and endosomal
microautophagy deliver small
cargoes directly to the lysosome
either without or with chaperones,
respectively.
Autophagy / Department of Pathological Physiology6
Types of Autophagy
Autophagy is recognized as a highly
selective cellular clearance pathway that is
associated with the maintenance of cellular
and tissue homeostasis.
Selective autophagy can be further divided
into many subtypes on the basis of the
specific cargos involved.
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy
aging and disease. Nat Aging 1, 634–650 (2021).
https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology7
Physiological Roles of Autophagy
At first autophagy activation was identified as the
response to starvation; currently, we know that
autophagy is activated in response to different
cellular stressors including exercise,
endoplasmic reticulum stress, infection, and
hypoxia.
Emerging results of the research are highlighting
the pivotal role of autophagic response in tissue
differentiation, functions, and remodeling after
stimuli.
Mizushima, N. and B. Levine, Autophagy in Human Diseases. New England Journal of Medicine, 2020. 383(16): p.
1564-1576.
Autophagy / Department of Pathological Physiology8
Function of Autopahgy
Autophagy plays an essential role
during the mammalian life cycle.
These functions span from
fertilization, cleavage, implantation,
fetal development, and postnatal
development, to the next
generation of gametogenesis,
indicating that autophagy has
important functions during the
whole mammalian life cycle.
At birth the trans-placental
nutrient supply is suddenly
interrupted, and neonates face
severe starvation until supply
can be restored through milk
nutrients. Neonates adapt to this
adverse circumstance by
inducing autophagy.
Autophagy / Department of Pathological Physiology9
Autophagy and immunity
Autophagy plays a crucial role in initiating and supporting
several processes in both innate and adaptive immunity.
ATG proteins directly contribute to pathogen clearance
through selective autophagy of microorganisms, coordinated
response with pattern recognition receptors, inflammasome
formation, antigen presentation, and LC3-associated
phagocytosis.
In adaptive immunity, autophagy modulates antigen
processing and presentation and regulates the development
of lymphocytes. Regulation of the organelle content of
lymphocytes, especially mitochondria, by autophagy is crucial
during differentiation.
Metur, S.P., Klionsky, D.J. Adaptive immunity at the crossroads of autophagy and metabolism. Cell Mol Immunol 18, 1096–1105 (2021). https://doi.org/10.1038/s41423-021-00662-3
The importance of autophagy for these functions is highlighted by the susceptibility of autophagy-deficient animals to infection
and the implication of autophagy defects in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis,
psoriasis, diabetes and multiple sclerosis
Autophagy / Department of Pathological Physiology10
Autophagy and Aging
Aging is a biological process that is characterized by time-dependent cellular and functional decline,
resulting in reduced quality of life for the organism.
Aging is the primary risk factor for the development of many disorders, including cardiovascular disease
(for example, stroke), cancer and neurodegenerative disease (for example, Alzheimer’s disease (AD)).
Among the many molecular changes associated with old age, altered autophagy has emerged as a
feature of aging across diverse species.
Compromised autophagy is a hallmark of aging
Autophagy / Department of Pathological Physiology11
Autophagy and Aging
Aging is associated with an accumulation of damage to subcellular organelles. Selective autophagy is the
common mechanism underlying the clearance of damaged and/or superfluous subcellular organelles such
as mitochondria (mitophagy), the ER (reticulophagy or ER-phagy), the nucleus (nucleophagy) and
lysosomes (lysophagy).
Gradual decline in the abundance of autophagy-related proteins and reduced delivery of cargo to
lysosomes occur with age, implicating compromised autophagy as a cardinal feature of organismal aging.
The mounting evidence that an imbalance of autophagy is an important age-associated characteristic has
driven extensive research into the development of compounds that can stimulate autophagy to promote
longevity.
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy aging and disease. Nat Aging 1, 634–650 (2021). https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology12
Autophagy and Aging
Examples of autophagy factors that can promote longevity.
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy aging and disease. Nat Aging 1, 634–650 (2021). https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology13
Autophagy and Aging
Summary of autophagy inducers that extend healthspan and increase lifespan in laboratory animals.
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy aging and disease. Nat Aging 1, 634–650 (2021). https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology14
Autophagy and Aging
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy aging and disease. Nat Aging 1, 634–650 (2021). https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology15
Autophagy in Health and Disease
Premature aging diseases with impaired mitophagy as a cause of
mitochondrial dysfunction, which contributes to short lifespan
(LS) and healthspan (HS).
ataxia telangiectasia (AT),
Cockayne syndrome (CS),
Fanconi anemia (FA),
Hutchinson–Gilford syndrome (HG),
Werner syndrome (WS) and xeroderma pigmentosum (XP;
especially group A).
Autophagy (including subtypes of selective autophagy, such as
mitophagy) is impaired in broad neurodegenerative diseases,
where impairment may drive or exacerbate disease progression.
Alzheimer's disease (A)D,
Parkinson’s disease (PD),
Huntington’s disease,
ALS,
frontotemporal dementia (FTD).
We emphasize that these are not the only drivers of the diseases
and other processes may have roles leading to pathology and
symptomatology.
Aman, Y., Schmauck-Medina, T., Hansen, M. et al. Autophagy in healthy aging and disease. Nat Aging 1, 634–650 (2021). https://doi.org/10.1038/s43587-021-00098-4
Autophagy / Department of Pathological Physiology16
Autophagy in Health and Disease
Mutations in autophagy-related
genes are now known to cause
mendelian disorders, and
autophagy gene polymorphisms
have been found to be associated
with susceptibility to some
diseases.
In the future, because autophagy
has a waste disposal function, its
activation and inhibition could be
a novel therapeutic strategy for
neurodegenerative diseases and
cancers.
Mizushima, N. and B. Levine, Autophagy in Human Diseases. New England Journal of Medicine, 2020. 383(16): p. 1564-1576.
Autophagy / Department of Pathological Physiology17
Complex roles of autophagy in cancer development and progression
Autophagy is an important process during cancer
progression, but the exact roles of autophagy in
cancer cells are strongly context-dependent.
Its cytoprotective function is believed to have
tumour-suppressive potential before the onset of
tumorigenesis, and loss of autophagy has been
associated with increased risk of cancer.
autophagy provides cancer cells with metabolic
plasticity, allowing them to thrive in suboptimal
environments and to exploit the pro-survival
activity of autophagy to cope with therapyinduced
stresses
autophagy induction is a side effect of many
cancer therapies, and thus, pharmacological
inhibition of autophagy has been proposed as
a valid strategy to enhance the efficacy of
therapies and to avoid resistance to treatment
in certain cancers
Mizushima, N. and B. Levine, Autophagy in Human Diseases. New England Journal of Medicine, 2020. 383(16): p.
1564-1576.
Autophagy / Department of Pathological Physiology18
Autophagy against neurodegenerative diseases
Autophagy protects against neurodegeneration by eliminating
two hallmarks of neurodegenerative diseases: defective
mitochondria and toxic protein aggregates.
Damaged mitochondria produce high levels of reactive oxygen
species (ROS) that pose a threat to many cellular components,
including proteins, lipids and DNA.
Protein aggregates, which are exacerbated by ROS-mediated
oxidative damage, compromise the function of organelles and
are considered particularly toxic for neurons.
Reduced autophagy activity (age-related, pharmacologically or
genetically caused) therefore increases the risk of
neurodegenerative diseases.
Pharmacological stimulation of autophagy could be an effective
therapeutic strategy against neurodegenerative diseases.
Autophagy / Department of Pathological Physiology19
Autophagy as a cell death modality?
It is controversial whether cells truly die via autophagy or whether — in dying cells — autophagy is merely an
innocent bystander or a well-intentioned ‘Good Samaritan’ trying to prevent inevitable cellular demise.
An aggressive form of autophagy termed autosis has been
described in cells following either ischemia/reperfusion injury or in
response to autophagy-inducing proteins like Tat-Beclin 1.
While it has not been demonstrated unambiguously that
autophagy drives cell death during development (Kroemer and
Levine, 2008), there is increasing evidence that ADCD is a bona
fide cell death program. Nevertheless, there are still major gaps in
our understanding of this mechanism in development and
pathogenesis.
Genetic models where an absolute requirement for the autophagic
machinery has been shown to be essential for cell
death: Dictyostelium discoideum, Drosofila melanogaster
Autophagy / Department of Pathological Physiology20
Coronavirus interactions with the cellular autophagy machinery
The viruses enter the host cell via endocytosis (they can do that also by
different mechanisms) and release their RNA into the cytosol;
this is followed by replicative translation with the membrane proteins
being made in the endoplasmic reticulum.
The newly formed viral particles may be released from the cell via
exocytosis, or they may then intersect with autophagy.
In general, autophagy plays an “antiviral” role, sequestering viral
structural proteins or even completely assembled viral particles within
autophagosomes; these will bind with lysosomes leading to
degradation of the cargo by lysosomal hydrolytic enzymes.
However, recent studies suggest that SARS-COV-2 disrupts and
hijacks the autophagy-lysosomal pathway and subverts it.
For example, the viral ORF3a protein may block autophagosomelysosome
fusion.
In addition, viral proteins may be delivered to a de-acidified lysosome
from which they can be released from the cell. This “proviral” role of the
disrupted autophagy process leads to extensive production and release
of the virus to the extracellular space causing the infection to spread to
non-infected cells.
Nastaran Samimi, Mojtaba Farjam, Daniel J. Klionsky & Nima Rezaei (2021) The role of autophagy in the pathogenesis of SARS-CoV-2 infection in different cell
types, Autophagy, DOI: 10.1080/15548627.2021.1989150