01-Nov-2017 - Max-Planck-Institut für Biochemie

Cellular power outage

Quality control in the mitochondria

A common feature of neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease are deposits of aggregated proteins in the patient's cells that cause damage to cellular functions. Scientists report that, even in normal cells, aberrant aggregation-prone proteins are continually produced due to partial failure of the respiratory system. Unless they are removed by degradation, aggregates accumulate preferentially in the mitochondria, the cellular power plants, ultimately blocking energy production. In order to get rid of these toxic aggregates, cells have developed an elaborate protein quality control system, which the researchers now describe in the journal Cell.

Misfolded proteins made from defective blueprints are often sticky and clump together. Accumulation of such faulty proteins is known to contribute to the progression of several diseases. Therefore, cells have internal quality control mechanisms that detect and rapidly destroy faulty proteins. Proteins are produced by ribosomes, and misfolding can occur if they stall while decoding a damaged template. If the necessary ribosome-associated quality control machinery (RQC) does not function properly, defective proteins accumulate and form toxic aggregates in the cytoplasm of the cells. A previous study reported that this aggregation mechanism is mediated by so-called CAT-tails – C-terminal alanine-threonine sequences that are added to the defective proteins. So far, studies have focused on how the RQC recognizes and clears blocked ribosomes in the cytosol. The collaborating groups at the MPIB and LMU have now investigated the clearance of ribosome-blocked proteins destined for the mitochondria.

Mitochondria are the cell’s power plants, converting the energy from nutrients into ATP. ATP is the universal “energy carrier” and is essential for all processes in living cells. Damage to the mitochondria thus has fatal consequences for cells. Their dysfunction not only plays a role in the development of metabolic diseases such as diabetes, but also in neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease. "This is why the mitochondria are also referred to as the 'Achilles' heel' of the cell," says Walter Neupert from the Department of Cell Biology at the LMU Biomedical Center. Neupert and his team have been studying mitochondria for a long time. They discovered that even normal, unstressed cells continually produce faulty proteins under respiratory conditions. Apparently, a side reaction in the respiratory system in the mitochondria causes them to steadily release reactive oxygen species that can damage DNA, RNA and proteins. To determine how aggregates can arise in mitochondria and cause damage to cells, they cooperated with the team led by F.-Ulrich Hartl at the Max Planck Institute of Biochemistry. Hartl has been investigating protein aggregates, a cellular cause of neurodegenerative diseases, for many years.

Faulty proteins inside mitochondria

“CAT-tailed proteins have a particularly toxic effect on mitochondrial function. Once CAT-tailed proteins are imported into the mitochondria, they form aggregates that may act as a seed, and ultimately bind proteins free of defects that have vital roles for the cell” explains Toshiaki Izawa, first author of the study, together with Sae-Hun Park. Among the latter are the mitochondrial chaperones and proteases, which – once clumped – can no longer efficiently perform their normal function of repairing the damaged proteins and eliminating faulty proteins. A vicious cycle begins, and eventually such aggregates can damage the molecular power plants and shut down ATP production.

The mitoRQC pathway

“The elimination by the degradation machinery in the cytoplasm of mitochondrial proteins that have been marked as faulty by the attachment of CAT-tails is tricky. The synthesis of these proteins in the cytosol is tightly coupled to their import into the mitochondria. Therefore, cells have developed another strategy to get rid of faulty mitochondrial proteins and maintain cellular homeostasis”, says Park. “We identified the cytosolic protein Vms1 as a key component of a novel pathway termed mitoRQC that protects mitochondria from the toxic effects of such aberrant proteins”, explain the authors of the study. Vms1 suppresses these toxic effects by reducing CAT-tailing of ribosome-stalled polypeptides, thereby preventing aggregation and directing aberrant polypeptides to intra-mitochondrial quality control systems. “Our results suggest a way in which mitochondrial toxicity may contribute to neurodegenerative diseases. These findings provide important novel insights into the mechanisms of cellular protein quality control as well as disease progression” Hartl concludes.

  • Izawa, T*., Park, S.H*., Zhao, L., Hartl, F.U., and Neupert, W.; "Cytosolic protein Vms1 links ribosome quality control to mitochondrial and cellular homeostasis"; Cell; October 2017; *These authors contributed equally to this work.

Facts, background information, dossiers

  • protein aggregates
  • neurodegenerative diseases
  • mitochondria
  • proteins
  • ribosomes

More about MPI für Biochemie

  • News

    New method revolutionizes cancer diagnosis

    How does cancer arise? How does cellular composition influence tumor malignancy? These questions are profound and challenging to answer, but are crucial to understand the disease and find the right cure. Now, a German-Danish team led by Professor Matthias Mann has developed a ground-breakin ... more

    MCM molecules impede the formation of DNA loops

    The entire genomic material of a cell must be packed into a tiny cell nucleus in such a way, that on the one hand, it can be stored in an organized manner and, on the other hand, it can be transcribed, duplicated or repaired as needed. Different proteins are responsible for space-saving pac ... more

    MaxDIA – taking proteomics to the next level

    Proteomics produces enormous amounts of data, which can be very complex to analyze and interpret. The free software platform MaxQuant has proven to be invaluable for data analysis of shotgun proteomics over the past decade. Now, Jürgen Cox, group leader at the Max Planck Institute of Bioche ... more

More about Max-Planck-Gesellschaft

  • News

    Neuroscientists illuminate how brain cells deep in the cortex operate in freely moving mice

    How can we see what neurons deep in the cortex are doing during behavior? Researchers at the Max Planck Institute for the Neurobiology of Behavior - caesar (MPINB) have developed a miniature microscope small enough to be carried on the head of a freely moving mouse and capable of measuring ... more

    Measuring Organ Development

    Researchers from Dresden and Vienna reveal link between connectivity of three-dimensional structures in tissues and the emergence of their architecture to help scientists engineer self-organising tissues that mimic human organs. Organs in the human body have complex networks of fluid-filled ... more

    Back to the Future of Photosynthesis

    The central biocatalyst in Photosynthesis, Rubisco, is the most abundant enzyme on earth. But how did Rubisco evolve, and how did it adapt to environmental changes during Earth’s history? By reconstructing billion-year-old enzymes, a team of Max Planck Researchers has deciphered one of the ... more

More about LMU

  • News

    Light-driven molecular swing

    When light impinges on molecules, it is absorbed and re-emitted. Advances in ultrafast laser technology have steadily improved the level of detail in studies of such light-matter interactions. FRS, a laser spectroscopy method in which the electric field of laser pulses repeating millions of ... more

    Secret structure in the wiring diagram of the brain

    In the brain, our perception arises from a complex interplay of neurons that are connected via synapses. But the number and strength of connections between certain types of neurons can vary. Researchers from the University Hospital Bonn (UKB), the University Medical Center Mainz and the Lud ... more

    Innate immunity: the final touch for antimicrobial defence

    If bacteria enter the body, it often takes just a few minutes for the innate immune system to recognise them as foreign and set the immune defence in motion. Receptors of the immune system that recognise bacterial cell wall components play a central role in this process. An important immune ... more

  • Authors

    Prof. Dr. Thomas Carell

    Thomas Carell graduated in chemistry, completing his doctorate at the Max Planck Institute for Medical Research under the tutelage of Prof. Dr Dr H. A. Staab. Following a research position in the USA, he accepted a position at ETH Zurich, setting up his own research group in the Laboratory ... more

q&more – the networking platform for quality excellence in lab and process

The q&more concept is to increase the visibility of recent research and innovative solutions, and support the exchange of knowledge. In the broad spectrum of subjects covered, the focus is on achieving maximum quality in highly innovative sectors. As a modern knowledge platform, q&more offers market participants one-of-a-kind networking opportunities. Cutting-edge research is presented by authors of international repute. Attractively presented in a high-quality context, and published in German and English, the original articles introduce new concepts and highlight unconventional solution strategies.

> more about q&more

q&more is supported by: