Fight Aging!

Aging is characterized by an increased presence in tissues of protein aggregates, solid deposits of misfolded proteins and metabolic waste. This increase is perhaps largely driven by the progressive damage and failure of mechanisms of clearance, such as those associated with the proteasome and lysosome, as well as the activities of the immune system. Here, researchers investigate the impact of aggregates on another vital cellular system, the mitochondria. In many age-related conditions characterized by the presence of aggregates and waste, mitochondrial dysfunction also occurs. Is this an example of independent aspects of aging correlating simply because the condition is age-related, or is there direct causation in this relationship?

Working with yeast and human cells, researchers 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. 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, 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 could help explain why protein clumping and mitochondrial deterioration are both hallmarks of neurodegenerative diseases. In a previous study, researchers 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. Testing this hypothesis was tricky, 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, the 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. 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). 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.

Biological systems are in general quite robust, but there are also some Achilles' heels that may be disease prone, 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.

Link: https://www.eurekalert.org/pub_releases/2017-03/jhm-icu022817.php