Cell Metab. doi:10.1016/j.cmet.2014.07.024

Mitochondrial proteins synthesized in the cytosol contain a cleavable N-terminal presequence that directs them to their destination. Upon arrival in the mitochondrion, the presequence peptide is removed by the processing peptidase MPP and subsequently degraded by the matrix peptidasome Cym1 (also known as PreP). In the mitochondria of yeast cym1 mutants, Mossmann et al. detected the accumulation of proteins containing the N-terminal presequence, suggesting that MPP activity was dependent on peptide degradation. The unprocessed proteins were identified as being required for mitochondrial processes such as ATP synthesis and respiration, which correlated with the defects observed in cym1 mutants, such as increased reactive oxygen species and decreased membrane potential. Interestingly, Cym1 was previously shown to degrade the amyloid-β peptide (Aβ), and the mitochondrial defects observed in cym1 mutants resembled features observed in Alzheimer's disease (AD) patients. The introduction of Aβ produced the same feedback effects on MPP activity as cym1 mutants with the accumulation of unprocessed mitochondrial proteins. Finally, the maturation of mitochondrial preproteins was also inhibited in mouse and human AD brain samples, suggesting a potentially conserved mechanism to explain the effects of Aβ peptide on mitochondrial function.