Carefully reviewed, the information included in the following two
documents explain the causes of a significant percentage of cancers that
has never before been elucidated; i.e. disruption of mitophagy; i.e.
failure to disassemble damaged organelles within cells. The process
takes out trash other than through autophagy.
Autophagy maintains intracellular waste removal for lipids - carbs and
amino acids. Mitophagy disassembles and recycles old organelles; e.g.
mitochondria and the endoplasmic reticulum.
The closest activity associated with the process is the use of drugs for
PD1 and PDL1 inhibition that cost $300,000 to $1,000, 000 per patient.
Note: If mitophagy fails to function, a second line of defense exists; i.e.
apoptosis. When apoptosis is disrupted, cancer cells are not killed and
they can multiply.
https://www.sciencedaily.com/releases/2016/12/161222143507.htm
Process cells use to destroy damaged organelles now
identified
Date:
December 22, 2016
Source:
UT Southwestern Medical Center
Summary:
Researchers have uncovered the mechanism that cells use to find and destroy an organelle
called mitochondria that, when damaged, may lead to genetic problems, cancer,
neurodegenerative diseases, inflammatory disease, and aging.
Researchers at UT Southwestern Medical Center have uncovered the
mechanism that cells use to find and destroy an organelle called mitochondria
that, when damaged, may lead to genetic problems, cancer,
neurodegenerative diseases, inflammatory disease, and aging.
Understanding how this process works could potentially lead to new treatments to prevent certain
illnesses and even some aspects of aging, said Dr. Beth Levine, Director of the Center for
Autophagy Research at UT Southwestern and senior author of the study, published in Cell. The
Center for Autophagy Research -- the only one of its kind in the nation -- investigates the process
called autophagy in which cells rid themselves of damaged or unnecessary components.
Mitochondria are commonly called the "powerhouses of the cell" because these cellular components
works like a tiny factory inside cells to convert compounds such as sugars into energy that a cell can
use.
But mitochondria also have a dark side: Because of their high-energy function, when they are
damaged, they release toxic chemicals called reactive oxygen species into the rest of the cell, said
Dr. Yongjie Wei, Assistant Professor of Internal Medicine at UT Southwestern and lead co-first
author of the study.
"The removal of damaged mitochondria by autophagy (a process called mitophagy) is important for
cellular health," said Dr. Levine, also Professor of Internal Medicine and Microbiology and a Howard
Hughes Medical Institute Investigator.
Researchers have to date focused on protein "tags" found on the outer membranes of mitochondria - especially the protein Parkin that attaches these tags -- to explain how the cell's degradative
organelles, called autophagosomes, target sick mitochondria, explained Dr. Levine, who holds the
Charles Cameron Sprague Distinguished Chair in Biomedical Science. (Autophagosomes are
double-membraned vesicles that contain cellular material to be degraded in the process called
autophagy.)
But UT Southwestern scientists, working with human and mouse cells, discovered that a receptor on
an inner mitochondrial membrane actually is more important in guiding these autophagosomes to
their prey.
In the study, researchers found that a protein called prohibitin 2 (PHB2) resides on the inner
membrane of mitochondria, but is exposed when an ailing mitochondrion's outer membrane
ruptures. Once the break occurs, the protein LC3, which rides on an autophagosome's exterior like a
lookout, is drawn to the PHB2.
The LC3 protein then attaches to PHB2, and the autophagosome carries its doomed cargo to a
lysosome -- yet another organelle found within cells -- that acts like a tiny stomach, with enzymes to
break down cell waste.
The study's finding that PHB2 is crucial in targeting mitochondria for autophagic degradation is new,
said Dr. Levine.
However, she said, previous research had linked the presence of PHB2 to prevention of cancer,
aging effects, neurodegeneration, and inflammation. So, given these beneficial health effects, it
makes sense that a key action of PHB2 is to help rid cells of damaging mitochondria that contribute
to such disease processes, she said.
"By understanding how cells get rid of damaged mitochondria that contribute to cancer,
neurodegenerative diseases, and aging, we may be able to develop treatments to prevent those
processes," Dr. Levine said.
The study also found that PHB2 is necessary for the routine elimination of paternal mitochondrial
DNA in developing embryos, leaving only mitochondrial DNA from the mother. This work was done
in roundworms, but a recent study performed elsewhere using mouse models demonstrated that
mitophagy is also used to remove paternal mitochondria in mammalian embryos, said Dr. WeiChung "Daniel" Chiang, a postdoctoral researcher at UT Southwestern and co-first author of the
study.
Usually, only maternal mitochondrial DNA is passed to offspring, Dr. Levine said. For unknown
reasons, the continued presence of paternal mitochondrial DNA signals genetic or health problems
in the progeny.
In yet another finding, the UTSW research shows that -- despite scientists' greater focus on the
Parkin protein's role in supporting autophagy -- PHB2 is required for Parkin to work.
Story Source:
Materials provided by UT Southwestern Medical Center. Note: Content may be edited for style and
length.
Journal Reference:
1. Yongjie Wei, Wei-Chung Chiang, Rhea Sumpter, Prashant Mishra, Beth Levine. Prohibitin 2 Is an
Inner Mitochondrial Membrane Mitophagy Receptor. Cell, 2016; DOI:10.1016/j.cell.2016.11.042
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Web address:
http://www.sciencedaily.com/releases/2013/
11/
131129101803.htm
Mitochondria Separate Their Waste
Nov. 29, 2013 — In order to protect themselves from harmful substances, cells need
to keep the mitochondria -- the boiler room, so to speak -- shipshape. Up to now, it
was unclear whether this housekeeping work involves sorting out defective proteins
when they digest mitochondria. Dr. Jörn Dengjel from the Center for Biological
Systems Analysis (ZBSA), Freiburg Institute for Advanced Studies (FRIAS), and the
Cluster of Excellence BIOSS Centre for Biological Signalling Studies of the
University of Freiburg has now discovered in collaboration with researchers from the
Hebrew University in Jerusalem, Israel, that the proteins are sorted out during the
constant fusion and fission of mitochondria. The team published their findings in the
journal Nature Communications.
The process of mitophagy, in which tiny digestive bubbles surround the mitochondria,
serves to recycle waste for the cell. Damaged proteins can no longer carry out their
function correctly and need to be broken down. Errors in the digestion of
mitochondria appear in old age and in the case of neurodegenerative diseases like
Parkinson's and Alzheimer's. A better understanding of mitophagy could be the key to
counteracting the faulty degradation of cellular components, potentially enabling
researchers to develop new therapies for neurodegenerative diseases. MCFIP – With
near certainty, these researchers are using the term mitophagy to describe the
mechanism of autophagy and the encapsulation in a lysosome as it applies to a
mitochondria that needs to be disassembled. Epigenetic signaling designations for the
process (also known as necroptosis) are TIMP1 -3, KLF4- 6 and PD1 – PDL1 and
PDL3.
In contrast to bacteria, yeast cells posses mitochondria and are also easy to grow in the
laboratory. The researchers used yeasts to observe the processes of mitophagy. Dr.
Hagai Abeliovich from the Hebrew University developed a new method for making
yeast cells digest mitochondria. Currently, researchers accomplish this by placing
stress on the cells with chemicals. With the new method, yeast cells in long-term
cultures begin digesting mitochondria of their own accord -- as soon as they have used
up all available nutrients. During mitophagy Dengjel succeeded in measuring whether
all proteins inside the mitochondria were broken down at the same speed. Indeed, the
cell broke down some proteins more quickly than others. When he observed the cells
under a fluorescence microscope, he ascertained that the marked proteins in the
mitochondria also behaved differently. They appear to be sorted. MCFIP – The
process of autophagy encompassing the activities related to proteins (i.e. chains of
amino acids), lipids and carbohydrates. Most likely this “sorting” is the process by
which each activity is accomplished. It should also be noted that terminology
problems exist; i.e. referencing signaling molecules that perform autophagy as
proteins.
The rules by which the sorting is carried out are as yet unknown. However, the
researchers demonstrated that mitochondrial dynamics are involved: Mitochondria
fuse and divide constantly, forming a network in the process. Genetically modified
yeasts that lack these dynamics but form small, round mitochondria exhibit no sorting
of the proteins. "The damaged proteins are sorted slowly into an area of the network
with each fusion and fission. This mitochondrion is marked and broken down," says
Dengjel. In other words, mitophagy plays the role of garbage collector, separating and
recycling waste for the cell. Now Dengjel wants to find out what characterizes the
proteins that are sorted out.
MCFIP – Actually, there are two separated mechanisms for recycling waste in cells;
i.e. autophagy using lysosomes for lipids, carbohydrates and amino acids and
mitophagy that uses a lysosome process with a different enzyme. Autophagy signaling
uses phagosomes in endocytosis while mitophagy uses a G-protein coupled receptor.