Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease

Wesley Peng; Leonie F. Schröder; Pingping Song; Yvette C. Wong; Dimitri Krainc

doi:10.1126/sciadv.adh3347

Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease

Wesley Peng, Leonie F. Schröder, Pingping Song, Yvette C. Wong, Dimitri Krainc^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson’s disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

Original language	English (US)
Article number	eadh3347
Journal	Science Advances
Volume	9
Issue number	29
DOIs	https://doi.org/10.1126/sciadv.adh3347
State	Published - Jul 21 2023

Funding

We thank all members of the Krainc laboratory for helpful advice. All imaging was performed at the Northwestern University Center for Advanced Microscopy supported by CCSF P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Transcriptomics services were performed by the Northwestern University NUSeq Core Facility. Metabolomics services were performed by the Northwestern University Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the following grants: National Institutes of Health AG066333 (W.P.), National Institutes of Health NS109252 (Y.C.W.), and National Institutes of Health NS122257 (D.K.).

ASJC Scopus subject areas

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title = "Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson{\textquoteright}s disease",

abstract = "Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson{\textquoteright}s disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.",

author = "Wesley Peng and Schr{\"o}der, {Leonie F.} and Pingping Song and Wong, {Yvette C.} and Dimitri Krainc",

note = "Funding Information: We thank all members of the Krainc laboratory for helpful advice. All imaging was performed at the Northwestern University Center for Advanced Microscopy supported by CCSF P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Transcriptomics services were performed by the Northwestern University NUSeq Core Facility. Metabolomics services were performed by the Northwestern University Metabolomics Core Facility at the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the following grants: National Institutes of Health AG066333 (W.P.), National Institutes of Health NS109252 (Y.C.W.), and National Institutes of Health NS122257 (D.K.). Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

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N2 - Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson’s disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

AB - Mutations in the E3 ubiquitin ligase parkin are the most common cause of early-onset Parkinson’s disease (PD). Although parkin modulates mitochondrial and endolysosomal homeostasis during cellular stress, whether parkin regulates mitochondrial and lysosomal cross-talk under physiologic conditions remains unresolved. Using transcriptomics, metabolomics and super-resolution microscopy, we identify amino acid metabolism as a disrupted pathway in iPSC-derived dopaminergic neurons from patients with parkin PD. Compared to isogenic controls, parkin mutant neurons exhibit decreased mitochondria-lysosome contacts via destabilization of active Rab7. Subcellular metabolomics in parkin mutant neurons reveals amino acid accumulation in lysosomes and their deficiency in mitochondria. Knockdown of the Rab7 GTPase-activating protein TBC1D15 restores mitochondria-lysosome tethering and ameliorates cellular and subcellular amino acid profiles in parkin mutant neurons. Our data thus uncover a function of parkin in promoting mitochondrial and lysosomal amino acid homeostasis through stabilization of mitochondria-lysosome contacts and suggest that modulation of interorganelle contacts may serve as a potential target for ameliorating amino acid dyshomeostasis in disease.

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Parkin regulates amino acid homeostasis at mitochondria-lysosome (M/L) contact sites in Parkinson’s disease

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