In cleaning up misfolded proteins, cell powerhouses can break down

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 .

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 , 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 . 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 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 , so the scientists used the same split-fluorescent 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 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

Related Stories

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

January 24, 2017
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.

Newly found mechanism for protecting neurons could underlie brain disease

February 9, 2017
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 problem—one ...

Misfolded proteins clump together in a surprising place

October 16, 2014
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 ...

Putting the squeeze on mitochondria: The final cut

October 31, 2016
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.

Recommended for you

Researchers find way to convert bad body fat into good fat

September 19, 2017
There's good fat and bad fat in our bodies. The good fat helps burn calories, while the bad fat hoards calories, contributing to weight gain and obesity. Now, new research at Washington University School of Medicine in St. ...

New model may help science overcome the brain's fortress-like barrier

September 19, 2017
Scientists have helped provide a way to better understand how to enable drugs to enter the brain and how cancer cells make it past the blood brain barrier.

Cell-based therapy success could be boosted by new antioxidant

September 19, 2017
Cell therapies being developed to treat a range of conditions could be improved by a chemical compound that aids their survival, research suggests.

Study suggests epilepsy drug can be used to treat form of dwarfism

September 19, 2017
A drug used to treat conditions such as epilepsy has been shown in lab tests at The University of Manchester to significantly improve bone growth impaired by a form of dwarfism.

Research predicts how patients are likely to respond to DNA drugs

September 19, 2017
Research carried out by academics at Northumbria University, Newcastle could lead to improvements in treating patients with diseases caused by mutations in genes, such as cancer, cystic fibrosis and potentially up to 6,000 ...

Urine output to disease: Study sheds light on the importance of hormone quality control

September 18, 2017
The discovery of a puddle of mouse urine seems like a strange scientific "eureka" moment.

0 comments

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

Click here to reset your password.
Sign in to get notified via email when new comments are made.