Amyloid-β Peptide Induces Mitochondrial Dysfunction by Inhibition of Preprotein Maturation

Abstract

Most mitochondrial proteins possess N-terminal presequences that are required for targeting and import into the organelle. Upon import, presequences are cleaved off by matrix processing peptidases and subsequently degraded by the peptidasome Cym1/PreP, which also degrades Amyloid-beta peptides (Aβ). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, Aβ inhibits degradation of presequence peptides by PreP, resulting in accumulation of mitochondrial preproteins and processing intermediates. Dysfunctional preprotein maturation leads to rapid protein degradation and an imbalanced organellar proteome. Our findings reveal a general mechanism by which Aβ peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer's disease.

Automated rapid iterative negative geotaxis assay and its use in a genetic screen for modifiers of Aβ42-induced locomotor decline in Drosophila

“…Interestingly, two enhancers (stock numbers 23714 and 24137) cover the same gene CG3731, whose protein product is a homolog of the mammalian peptidase (mitochondrial processing) beta (PMPCB). The inhibition of its processing of the presequences of mitochondrial proteins was proposed to be a general mechanism for diverse Aβ-induced mitochondrial dysfunctions [12] . Nevertheless, it should be pointed out that the genetic backgrounds of the deficient lines might differ from each other, and from wild-type and Aβ arc flies, so further experiments are needed to validate these suppressors and enhancers.…”

Quantitative Profiling for Substrates of the Mitochondrial Presequence Processing Protease Reveals a Set of Nonsubstrate Proteins Increased upon Proteotoxic Stress

“…To distinguish if this is a special characteristic of these particular non-processed proteins or a general feature of mas1 mitochondria we chose the control proteins Hsp10, which is not processed upon import into the mitochondrial matrix, and Mrpl32, that is processed by the m-AAA protease but not by MPP. 15,37 Both, Hsp10 and…”

“…Deletion of proteases in different organisms for in vivo analysis or purified proteases incubated with cell lysates allowed specific substrate identification of an individual protease 5,15,42,45. However, the in vivo analysis of essential proteases was not feasible so far due to the lack of a model system possessing a specifically impaired protease activity.…”

Amary llidaceae Perspectives In Alzheimer´S Disease

“…Nevertheless, recent studies suggest that the oligomers of the Aβ peptide are more toxic than their monomeric and fibrillary aggregates and although the molecular mechanisms that lead to the disease are not well understand, sufficient evidence regarding the role of oxidative stress and mitochondrial dysfunction in AD are recognized as early events in the development of the disease [32]. It has been shown that Aβ peptide gains access into mitochondrial matrix and its progressively accumulates mediates mitochondrial stress by interfering with enzyme activity, affecting the neural bioenergetics, an important pathway in the pathogenesis of this devastating disease [33,34].…”