Autophagy research Yoshinori Ohsumi

1. The Nobel Prize in
Medicine and
Physiology in 2016

2. Introduction to Autophagy.
Autophagy is a normal physiological process in the body that deals with
destruction of cells in the body.
The name stems from the Ancient Greek autóphagos, meaning "self-devouring".
It maintains homeostasis or normal functioning by protein degradation and
turnover of the destroyed cell organelles for new cell formation.

3. Introduction continued...
The concept of autophagy first arose in 1960’s where by researchers discovered that cells were able to
close their membranes and destroy the content within.
Autophagy consists of several sequential steps—sequestration, transport to lysosomes, degradation,
and utilization of degradation products—and each step may exert different function.
Autophagy is mediated by a unique organelle called the autophagosome. As autophagosomes engulf a
portion of cytoplasm, autophagy is generally thought to be a nonselective degradation system.
Many issues emerged when trying to study the physiological process so little was discovered until
Yoshinori Ohsumi devised several excellent experiments in the early 1990’s.

4. History of Autophagy
•An Autophagosome is known as a ‘self eating’ cell . It first started to be researched in the 1960s;
when it was noticed that cells could destroy their own contents by enclosing its own membranes
forming sack-like vesicles, that is then transported to lysosome for degradation.
•In 1992 Yoshinori Ohsumi used baker’s yeast to identify genes essential for autophagy. He published
the discovery that when the cell vacuole is starved and the autophagosome lacks nutrients, the
autophagosome does not degrade.
•He identified 15 genes essential for the formation of the autophagosome. Mainly genes responsible
for proteins and protein complexes that
function as regulators in the stages of autophagy.

5. History of Autophagy

6. Experiment
When Yoshinori started his own lab 1998 he focused his research on protein
degradation.
He used yeast cells due to their similar eukaryotic structure to human cells.
But wasn’t sure if autophagy existed within this organelle
This is because the inner components of the cell
are too small to identify under a microscope

7. Experiment continued...
So he disrupted the protein degradation
process!
This is to see if autophagosomes
would accumulate within the yeast cell,
proving that autophagy occurs.
He cultured yeast that lacked the
degradation enzymes and starved the
cells to stimulate autophagy.
The results proved that autophagy did occur because autophagosomes did
accumulate!

8. Types of Autophagy
3 SUBTYPES: MICROAUTOPHAGY, MACROAUTOPHAGY
AND CHAPERONE- MEDIATED AUTOPHAGY
1) MACROAUTOPHAGY: membrane forms around
material to be digested before fusing with the lysosome:
- Most broadly explored
- Degrades % of cytoplasm and cellular organelles
SELECTIVE AUTOPHAGY: deals with cytoplasmic
organelles, viruses, bacteria and proteins
NON- SELECTIVE AUTOPHAGY: induced in response to
stress e.g. starvation conditions

9. Types of Autophagy cont.
2) MICROAUTOPHAGY: material needed to be digested
diffuses directly within the lysosome
- Inward folding
- Generally non- selective
- Involves direct engulfment of cytoplasmic cargo
3) CHAPERONE- MEDIATED AUTOPHAGY (cma): has
substrate proteins targeted to lysosomes via chaperone
complexes on both sides of the membrane.
- Cytosolic proteins target lysosomes and are transferred
across the lysosome membrane for degradation
- Aids cellular QC
- Evidence that neurodegeneration & cancer are
contributed to by CMA dysfunction

10. Autophagy in Health & Disease
Discoveries by Ohsumi have led to the understanding of how autophagy can have major
implications and benefits for human health and disease.
Autophagy plays an essential role in:
● maintenance of cellular homeostasis
● cell differentiation and embryogenesis
Cytoprotective functions of autophagy:
● protect cells from harm
● counteract cell injury and diseases associated with ageing e.g. Parkinson’s disease
and also type 2 diabetes.

11. Autophagy in Health & DiseaseAutophagy and the immune system:
● Autophagy is a component in the immune
defenses in macrophages against
bacterial and viral infections
● Elimination of pathogens by Xenophagy
Exploitation of autophagy by viruses and
bacteria for growth and survival.
Autophagy promotes cell survival but also
cell death, linking autophagy to
pathological conditions such as
neurodegenerative diseases, cancer and
infections.
Autophagy and cancer:
Mutations in autophagy genes and disruption
of autophagic machinery linked to the
development of cancers.
Autophagy plays a substantial role in the
initiation and progression of cancers.
● Beclin-1 mutations in many cases of
breast and ovarian cancer.
Autophagy plays a role in tumour progression
& dormancy and resistance to anticancer
therapies.