24:T40c,PINK1, mutated in familial forms of Parkinson's disease, initiates mitophagy following mitochondrial depolarization. However, it is difficult to monitor this pathway physiologically in mice as loss of PINK1 does not alter basal mitophagy levels in most tissues. To further characterize this pathway in vivo, we used mito-QC mice in which loss of PINK1 was combined with the mitochondrial-associated POLG^D257A mutation. We focused on skeletal muscle as gene expression data indicates that this tissue has the highest PINK1 levels. We found that loss of PINK1 in oxidative hindlimb muscle significantly reduced mitophagy. Of interest, the presence of the POLG^D257A mutation, while having a minor effect in most tissues, restored levels of muscle mitophagy caused by the loss of PINK1. Although our observations highlight that multiple mitophagy pathways operate within a single tissue, we identify skeletal muscle as a tissue of choice for the study of PINK1-dependant mitophagy under basal conditions.25:T52c,The ability to adapt the proteolysis rates based on fluctuations in essential amino acid (EAA) availability is essential for life. The GCN2-eIF2α-ATF4 signaling pathway is involved in the adaptive response to EAA deprivations. Our previous results demonstrated that activation of this pathway is involved in upregulating the expression of many autophagy genes at the transcriptional level thanks to the transcription factor ATF4. In the present study, we investigated whether the kinase GCN2 is also involved in early upregulation of the autophagic process in response to EAA deficiencies, thereby contributing to a rapid increase in the proteolysis rate. We observed that a one-hour leucine deprivation upregulated autophagy in both cultured cells and in vivo in mouse liver, as reflected by an increase in both [S278]-ATG16L1 phosphorylation and LC3B conversion, and decreased p62 protein level. Using cells and mice with genetic ablation of Gcn2 as well as genetic reconstitution experiments in vitro, data showed that GCN2 was required for this upregulation of autophagy. Downstream GCN2, the phosphorylation of eIF2α was necessary, while ATF4 was not. Overall, these findings revealed a major role of GCN2-eIF2α signaling in the regulation of autophagy in response to short-term EAA deprivation.26:T5c0,

#	Concept	H-Index	Publications	Citations
1	Medicine	4	4	88
2	Cell Biology	4	4	88
3	Engineering	1	1	28
4	Natural Sciences	1	1	12
5	Biology	1	1	28

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