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

作者：Mossmann Dirk; Voegtle F Nora; Taskin Asli Aras; Teixeira Pedro Filipe; Ring Julia; Burkhart Julia M; Burger Nils; Pinho Catarina Moreira; Tadic Jelena; Loreth Desiree; Graff Caroline; Metzger Friedrich; Sickmann Albert; Kretz Oliver; Wiedemann Nils; Zahedi Rene P; Madeo Frank; Glaser Elzbieta; Meisinger Chris^*

来源：Cell Metabolism, 2014, 20(4): 662-669.

DOI：10.1016/j.cmet.2014.07.024

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 (A beta). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, A beta 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 A beta peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer%26apos;s disease.

• 出版日期2014-10-7