Figure 14.

The Q311X parkin mutation impacts on mitochondrial quality control by interfering with PARIS-mediated regulation of PGC1α-TFEB signaling, which can be independently restored by rapamycin in a TFEB-dependent fashion. Our data suggest that compromise of parkin E3 ligase activity in Q311X-expressing mutants results in increased PARIS levels and reductions in master PGC1α-TFEB signaling. This impacts in turn on mitochondrial quality control via effects on both mitochondrial and lysosomal biogenesis and function. Independent induction of TFEB activity by rapamycin can restore this signaling pathway along with abrogating detrimental effects of the Q311X mutation on mitochondrial function and neuronal cell viability.