Amyloid-? peptide induces mitochondrial dysfunction by inhibition of preprotein maturation
28.08.2014
Mossmann D, Vögtle FN, Taskin AA, Teixeira PF, Ring J, Burkhart JM, Burger N, Pinho CM, Tadic J, Loreth D, Graff C, Metzger F, Sickmann A, Kretz O, Wiedemann N, Zahedi RP, Madeo F, Glaser E, Meisinger C.
Cell Metab. 2014 Oct 7;20(4):662-9
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 that also degrades Amyloid-beta peptides (A?). Here we find that impaired turnover of presequence peptides results in feedback inhibition of presequence processing enzymes. Moreover, A? 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 how A? peptide can induce the multiple diverse mitochondrial dysfunctions accompanying Alzheimer’s disease.
