Transcriptional regulation of Insulin Degrading Enzyme modulates mitochondrial Aâ catabolism and functionality.

LEAL M.C; MAGNANI, N; VILLORDO S; MARINO BUSLJE MC; EVELSON, P; CASTAñO E.M; MORELLI L

JOURNAL OF BIOLOGICAL CHEMISTRY (ONLINE)

HighWire Press

Año: 2013 p. 1 - 11

1083-351X

Studies of post-mortem brains from Alzheimer disease patients suggest that oxidative damage induced by mitochondrial amyloid â (mitAâ) accumulation is associated with mitochondrial dysfunction. However, the regulation of mitAâ metabolism is unknown. One of the proteases involved in mitAâ catabolism is the long insulin-degrading enzyme (IDE) isoform (IDE-Met(1)). However, the mechanisms of its expression are unknown, and its presence in brain is uncertain. We detected IDE-Met(1) in brain and showed that its expression is regulated by the mitochondrial biogenesis pathway (PGC-1á/NRF-1). A strong positive correlation between PGC-1á or NRF-1 and long IDE isoform transcripts was found in non-demented brains. This correlation was weaker in Alzheimer disease. In vitro inhibition of IDE increased mitAâ and impaired mitochondrial respiration. These changes were restored by inhibition of ã-secretase or promotion of mitochondrial biogenesis. Our results suggest that IDE-Met(1) links the mitochondrial biogenesis pathway with mitAâ levels and organelle functionality.