Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo.
Oligodendrocytes, the myelinating cells of the central nervous system, are essential for correct brain function. They originate from oligodendrocyte precursor cells through a differentiation process which is only incompletely understood and impaired in a variety of demyelinating diseases. Better knowledge of this differentiation holds the promise to develop novel therapies for these disorders. The differentiation of rat oligodendrocyte precursor cells to oligodendrocytes in vitro is investigated. After confirmation of differentiation by immunohistochemical analysis using cell type-specific marker proteins, a quantitative proteomics study using tandem mass tagsTMT) is conducted. Four time points of differentiation covering early, intermediate, and late stages are investigated. Data analysis by Mascot and MaxQuant identified 5259 protein groups of which 471 are not described in the context of cells of the oligodendroglial lineage before. Quantitative analysis of the dataset revealed distinct regulation patterns for proteins of different functional categories including metabolic processes, regulation of the cell cycle, and transcriptional control of protein expression. The present data confirm a significant number of proteins known to play a role in oligodendrocytes and myelination. Furthermore, novel candidate proteins are identified which may play an important role in this differentiation process providing a valuable resource for oligodendrocyte research.
PTEN-induced putative kinase 1 (PINK1) is a mitochondria-targeted kinase whose mutations are a cause of Parkinson’s disease. We set out to better understand PINK1’s effects on mitochondrial proteins in vivo. Using an unbiased phosphoproteomic screen in Drosophila, we found that PINK1 mediates the phosphorylation of MCAD, a mitochondrial matrix protein critical to fatty acid metabolism. By mimicking phosphorylation of this protein in a PINK1 null background, we restored PINK1 null’s climbing, flight, thorax, and wing deficiencies. Owing to MCAD’s role in fatty acid metabolism, we examined the metabolic profile of PINK1 null flies, where we uncovered significant disruptions in both acylcarnitines and amino acids. Some of these disruptions were rescued by phosphorylation of MCAD, consistent with MCAD’s rescue of PINK1 null’s organismal phenotypes. Our work validates and extends the current knowledge of PINK1, identifies a novel function of MCAD, and illuminates the need for and effectiveness of metabolic profiling in models of neurodegenerative disease.
DOI: https://doi.org/10.1002/pmic.201900057 Oligodendrocytes, the myelinating cells of the central nervous system, are generated by differentiation of oligodendrocyte precursor cells through mechanisms which are only incompletely understood. This process is pathogenetically relevant for several diseases affecting myelin, and a better understanding holds the promise to develop novel therapeutic approaches. In article number 1900057, Schoor et al. investigate oligodendrocyte precursor cell differentiation by quantitative proteomics. Their results identify proteins, which are regulated with distinct patterns during the transition from precursor cells to oligodendrocytes, and are therefore potentially involved in basic cellular functions of the individual cell types and their differentiation.
Oligodendrocytes are generated via a two-step mechanism from pluripotent neural stem cells (NSCs): after differentiation of NSCs to oligodendrocyte precursor/NG2 cells (OPCs), they further develop into mature oligodendrocytes. The first step of this differentiation process is only incompletely understood. In this study, we utilized the neurosphere assay to investigate NSC to OPC differentiation in a time course-dependent manner by mass spectrometry-based (phospho-) proteomics. We identify double cortin like kinase 1 (Dclk1) as one of the most prominently regulated proteins in both datasets, and show that it undergoes a gradual transition between its short/long isoform during NSC to OPC differentiation. This is regulated by phosphorylation of its SP-rich region, resulting in inhibition of proteolytic Dclk1 long cleavage, and therefore Dclk1 short generation. Through interactome analyses of different Dclk1 isoforms by proximity biotinylation, we characterize their individual putative interaction partners and substrates.
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