Defects in mitochondria can buildup Alzheimer's-related proteins

- Posted in English by

Mitochondria are organelles that have their own genomes, which are small and only encode 13 proteins, compared to around 20,000 for the genome of human cells. enter image description here By National Human Genome Research Institute - via Wikipedia

More than 1000 proteins are used by the mitochondria to perform their functions, the mitochondria therefore rely on the importation of proteins encoded in the nucleus of the host cell. The majority of mitochondrial proteins are synthesized in the cytosol and must be actively transported to the mitochondria, a process that occurs via a sophisticated system.

In many neurodegenerative diseases, there are dysfunctions in the management of proteins. This is called proteopathies. Proteopathies are found in diseases such as Creutzfeldt-Jakob disease and other prion diseases, Alzheimer's disease, Parkinson's disease, ALS and a wide range of other disorders.

Since proteins share a common structure known as the polypeptide backbone, all proteins have the potential to fold badly under certain circumstances. Mitochondrial defects might be responsible in part for those misfolded proteins that accumulate in the cytosol.

However, it is still unclear whether mitochondrial defects appear as a consequence of neurodegeneration, or if they contribute to it, or both. Since the accumulated mitochondrial protein precursors can form toxic aggregates, host cells have a mechanism to respond to and cope with them properly.

In an excellent eLife publication, Urszula Nowicka and colleagues at the University of Warsaw hypothesized that mitoprotein-induced stress induces a general response to precursor proteins which then accumulate in the cytosol and this contributes to the onset and progression neurodegenerative disorders. In this study, the authors propose a new mechanism of proteostasis.

Studies have shown that specific mitochondrial proteins that are functionally related to oxidative phosphorylation are downregulated by transcription in Alzheimer's disease. In the present study, scientists at the University of Warsaw investigated why these proteins are downregulated.

They used yeast homologues of these proteins to show the consequences of this cytosolic accumulation as well as of C. elegans worms. They applied mutations to the import machines, overexpression of mitochondrial proteins and CCCP (a decoupler of oxidative phosphorylation). They studied two disease-relevant aggregation models - α synuclein and Amyloid beta aggregation.

They found that importation of compromised mitochondrial proteins caused overall changes in the levels of transcriptome and proteins, especially chaperones, including Hsp104 and Hsp42, ABC transporters and mitochondrial proteins, which can lead to growth defects. (yeast) and decreased motility (C. elegans).

This new hypothesis complements the recent findings very well that unprocessed (but imported!) Precursor proteins aggregate in the mitochondrial matrix and initiate an mtUPR-like response.

These proteins trigger a molecular chaperone response specific to the host cell that aims to minimize the consequences of protein aggregation. However, when this rescue mechanism is insufficient, these aggregates stimulate cytosolic aggregation of other mitochondrial proteins and lead to downstream aggregation of non-mitochondrial proteins.

The present study showed that a group of mitochondrial proteins that are downregulated in Alzheimer's disease (i.e. Rip1, Atp2, Cox8 and Atp20) can aggregate in the cytosol and that the overexpression of these proteins upregulates Hsp42 and Hsp104, two molecular chaperones. Cellular stress responses induced by mitochondrial proteins mitigate the danger.

Urszula Nowicka's findings indicate why and how metastable mitochondrial proteins can be downregulated during neurodegeneration to minimize the imbalance in cellular protein homeostasis caused by their poor targeting.

Several stress response pathways have recently been identified to counteract import defects in mitochondrial proteins. It is not known, however, whether they act independently or whether simultaneous actions of all of these stress responses are necessary to ensure balanced homeostasis of cellular proteins.

It is likely that the study of the mechanisms of protection against stress, whether at the cellular level or at the mitochondrial level, will make it possible to better understand neurodegenerative diseases and to develop drugs to treat them.


This book retraces the main achievements of ALS research over the last 30 years, presents the drugs under clinical trial, as well as ongoing research on future treatments likely to be able stop the disease in a few years and to provide a complete cure in a decade or two.

Please, to help us continue to provide valuable information: