Defective mitochondrial quality control is shown to be a mechanism for neurodegeneration in some forms of Parkinson's disease.

Eukaryotes employ elaborate mitochondrial quality control (MQC) to maintain the function of the power-generating organelle. Parkinson's disease-associated PINK1 and Parkin actively participate in MQC. However, the signaling events involved are largely unknown. Here we show that mechanistic target of rapamycin 2 (mTORC2) and Tricornered (Trc) kinases act downstream from PINK1 to regulate MQC. Trc is phosphorylated in mTORC2-dependent and mTORC2-independent manners and is specifically localized to mitochondria in response to PINK1, which regulates mTORC2 through mitochondrial complex-I activity. Genetically, mTORC2 and Trc act upstream of Parkin. Thus, multiplex kinase signaling is acting between PINK1 and Parkin to regulate MQC, a process highly conserved in mammals.Supplemental material is available for this article. We continued using the powerful tools available in Drosophila to dissect the genetic program underlying PINK1/Parkin-directed MQC. Here we identify mechanistic target of rapamycin 2 (mTORC2) and tricornered (Trc) kinase signaling as intermediate steps between PINK1 and Parkin in the MQC process in Drosophila and further verify the findings in mammalian cells. Our results reveal a previously unanticipated complexity of signaling events involved in PINK1/Parkin-directed MQC and tissue maintenance and shed new light on how mTORC2 and Trc, two important kinases critically involved in cellular morphogenesis, development, growth, and disease, are regulated in an in vivo setting. Results and DiscussionTo elucidate the signaling events acting downstream from PINK1, we performed genetic screens as described before (Liu and Lu 2010;Liu et al. 2012) to identify genes that can modify PINK1 loss-of-function (LOF)-induced wing posture and flight ability defects. This led to the identification of mTORC2 components as strong modifiers of PINK1. While overexpression of the mTORC2 components Rictor and Sin1 (Hietakangas and Cohen 2007), either individually or in combination, had no obvious effects on their own (Supplemental Fig. S1), they effectively suppressed dPINK1 LOF phenotypes with respect to the integrity and function of flight muscle, as measured by thoracic ATP level and wing posture (Fig. 1A,B;Supplemental Fig. S1D) and the loss of dopaminergic neurons (DNs) in the PPL1 cluster (Fig. 1E). Conversely, rictor or sin1 mutations significantly enhanced dPINK1 LOF phenotypes ( Fig. 1A-E; Supplemental Fig. S1D), although the rictor or sin1 mutant alone did not show obvious phenotypes in these assays (Supplemental Fig. S1A-C). The effects of mTORC2 components on tissue integrity correlated well with the effects on mitochondrial morphology, with mTORC2 gain of function (GOF) rescuing the mitochondrial aggregation phenotype caused by dPINK1 LOF, whereas mTORC2 LOF had opposite effects (Fig. 1C,D).We next explored the molecular mechanisms underlying the strong genetic interaction between PINK1 and mTORC2. Using phosphorylation of Drosophila AKT at S505 as readout of mTORC2 activity (Sarbassov et al.

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Edited by Jesus AvilaKeywords: Parkin PDCD2-1 Apoptosis Ubiquitin-proteasome system Substantia nigra a b s t r a c t Mutations in parkin gene are responsible for autosomal recessive Parkinson's disease (ARPD) and its loss-of-function is assumed to affect parkin ubiquitin ligase activity. Accumulation of its substrate may induce dopaminergic neurodegeneration in the substantia nigra (SN) of ARPD. Here, we show that parkin interacts with programmed cell death-2 isoform 1 (PDCD2-1) and promotes its ubiquitination. Furthermore, accumulation of PDCD2-1 was found in the SN of ARPD as well as in sporadic PD, suggesting that common failure of the ubiquitin-proteasome system is associated with neuronal death in both ARPD and sporadic PD.

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