In cleaning up misfolded proteins, cell powerhouses can break down – Medical Xpress

March 1, 2017 Mitochondria (red) that have imported misfolded proteins (green). Credit: Erli Jin and Linhao Ruan/Johns Hopkins Medicine

Working with yeast and human cells, researchers at Johns Hopkins say they have discovered an unexpected route for cells to eliminate protein clumps that may sometimes be the molecular equivalent of throwing too much or the wrong trash into the garbage disposal. Their finding, they say, could help explain part of what goes awry in the progression of such neurodegenerative diseases as Parkinson's and Alzheimer's.

Proteins in the cell that are damaged or folded incorrectly tend to form clumps or aggregates, which have been thought to dissolve gradually in a cell's cytoplasm or nucleus thanks to an enzyme complex called the proteasome, or in a digestive organelle called the lysosome.

But in experiments on yeast, which has many structures similar to those in human cells, the Johns Hopkins scientists unexpectedly found that many of those protein clumps break down in the cell's energy-producing powerhouses, called mitochondria. They also found that too many misfolded proteins can clog up and damage this vital structure.

The team's findings, described March 1 in Nature, could help explain why protein clumping and mitochondrial deterioration are both hallmarks of neurodegenerative diseases.

Rong Li, Ph.D., professor of cell biology, biomedical engineering and oncology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center, who led the study, likens the disposal system to the interplay between a household's trash and a garbage disposal in the kitchen sink. The disposal is handy and helps keep the house free of food scraps, but the danger is that with too much trash, especially tough-to-grind garbage, the system could get clogged up or break down.

In a previous study, Li and her team found protein aggregates, which form abundantly under stressful conditions, such as intense heat, stuck to the outer surface of mitochondria. In this study, they found the aggregates bind to proteins that form the pores mitochondria normally use to import proteins needed to build this organelle. If these pores are damaged by mutations, then aggregates cannot be dissolved, the researchers report. These observations led the team to hypothesize that misfolded proteins in the aggregates are pulled into mitochondria for disposal, much like food scraps dropped into the garbage disposal. Testing this hypothesis was tricky, Li says, because most of the misfolded proteins started out in the cytoplasm, and most of those that enter mitochondria quickly get ground up.

As a consequence, Li and her team used a technique in which a fluorescent protein was split into two parts. Then, they put one part inside the mitochondria and linked the other part with a misfolded and clumping protein in the cytoplasm. If the misfolded protein entered the mitochondria, the two parts of the fluorescent protein could come together and light up the mitochondria. This was indeed what happened.

"With any experiment," Li says, "you have a hypothesis, but in your head, you may be skeptical, so seeing the bright mitochondria was an enlightening moment."

To see what might happen in a diseased system, the team then put into yeast cells a protein implicated in the neurodegenerative disease known as amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease. After a heat treatment that caused the ALS protein to misfold, it also wound up in the mitochondria. The researchers then did an experiment in which a lot of proteins in the cytoplasm were made to misfold and found that when too much of these proteins entered mitochondria, they started to break down.

The team wanted to make sure that the phenomenon it had observed in the yeast cells could also happen in human cells, so the scientists used the same split-fluorescent protein method to observe misfolded proteins to enter the mitochondria of lab-grown human retinal pigmented epithelial cells. As observed in yeast, misfolded proteins, but not those that were properly folded, entered and lit up mitochondria.

Biological systems are in general quite robust, but there are also some Achilles' heels that may be disease prone, Li says, and relying on the mitochondrial system to help with cleanup may be one such example. While young and healthy mitochondria may be fully up to the task, aged mitochondria or those overwhelmed by too much cleanup in troubled cells may suffer damage, which could then impair many of their other vital functions.

Explore further: Cell disposal faults could contribute to Parkinson's, study finds

More information: Linhao Ruan et al, Cytosolic proteostasis through importing of misfolded proteins into mitochondria, Nature (2017). DOI: 10.1038/nature21695

A fault with the natural waste disposal system that helps to keep our brain cell 'batteries' healthy may contribute to neurodegenerative disease, a new study has found.

To stay healthy, neurons must prevent protein aggregates and defective organelles such as mitochondria from accumulating inside them. We now know that an animal species has found a solution to its neuronal trash problemone ...

Scientists at the Stowers Institute for Medical Research have made a surprising finding about the aggregates of misfolded cellular proteins that have been linked to aging-related disorders such as Parkinson's disease. The ...

A new University of Colorado Boulder study shows for the first time the final stages of how mitochondria, the sausage-shaped, power-generating organelles found in nearly all living cells, regularly divide and propagate.

A French teen who was given gene therapy for sickle cell disease more than two years ago now has enough properly working red blood cells to dodge the effects of the disorder, researchers report.

A research team, led by the University of Minnesota, has discovered a groundbreaking process to successfully rewarm large-scale animal heart valves and blood vessels preserved at very low temperatures. The discovery is a ...

Working with yeast and human cells, researchers at Johns Hopkins say they have discovered an unexpected route for cells to eliminate protein clumps that may sometimes be the molecular equivalent of throwing too much or the ...

By changing one small portion of a stimulus that influences part of one molecule's function, engineers and researchers at Washington University in St. Louis have opened the door for more insight into how the molecule is associated ...

A minimally invasive, fiber-optic technique that accurately measures the passive stretch and twitch contraction of living muscle tissue could someday be an alternative to the painful muscle biopsies used to diagnose and treat ...

An in-depth computational analysis of genetic variants implicated in both schizophrenia and rheumatoid arthritis by researchers at the University of Pittsburgh points to eight genes that may explain why susceptibility to ...

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

See original here:
In cleaning up misfolded proteins, cell powerhouses can break down - Medical Xpress