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Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis.
Autophagy. 2019 09; 15(9):1572-1591.A

Abstract

Mitochondria are key organelles for cellular metabolism, and regulate several processes including cell death and macroautophagy/autophagy. Here, we show that mitochondrial respiratory chain (RC) deficiency deactivates AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis) signaling in tissue and in cultured cells. The deactivation of AMPK in RC-deficiency is due to increased expression of the AMPK-inhibiting protein FLCN (folliculin). AMPK is found to be necessary for basal lysosomal function, and AMPK deactivation in RC-deficiency inhibits lysosomal function by decreasing the activity of the lysosomal Ca2+ channel MCOLN1 (mucolipin 1). MCOLN1 is regulated by phosphoinositide kinase PIKFYVE and its product PtdIns(3,5)P2, which is also decreased in RC-deficiency. Notably, reactivation of AMPK, in a PIKFYVE-dependent manner, or of MCOLN1 in RC-deficient cells, restores lysosomal hydrolytic capacity. Building on these data and the literature, we propose that downregulation of the AMPK-PIKFYVE-PtdIns(3,5)P2-MCOLN1 pathway causes lysosomal Ca2+ accumulation and impaired lysosomal catabolism. Besides unveiling a novel role of AMPK in lysosomal function, this study points to the mechanism that links mitochondrial malfunction to impaired lysosomal catabolism, underscoring the importance of AMPK and the complexity of organelle cross-talk in the regulation of cellular homeostasis. Abbreviation: ΔΨm: mitochondrial transmembrane potential; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATP: adenosine triphosphate; ATP6V0A1: ATPase, H+ transporting, lysosomal, V0 subbunit A1; ATP6V1A: ATPase, H+ transporting, lysosomal, V0 subbunit A; BSA: bovine serum albumin; CCCP: carbonyl cyanide-m-chlorophenylhydrazone; CREB1: cAMP response element binding protein 1; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; EBSS: Earl's balanced salt solution; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide-p-trifluoromethoxyphenolhydrazone; GFP: green fluorescent protein; GPN: glycyl-L-phenylalanine 2-naphthylamide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryonic fibroblast; MITF: melanocyte inducing transcription factor; ML1N*2-GFP: probe used to detect PtdIns(3,5)P2 based on the transmembrane domain of MCOLN1; MTORC1: mechanistic target of rapamycin kinase complex 1; NDUFS4: NADH:ubiquinone oxidoreductase subunit S4; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; pcDNA: plasmid cytomegalovirus promoter DNA; PCR: polymerase chain reaction; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; P/S: penicillin-streptomycin; PVDF: polyvinylidene fluoride; qPCR: quantitative real time polymerase chain reaction; RFP: red fluorescent protein; RNA: ribonucleic acid; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; shRNA: short hairpin RNA; siRNA: small interfering RNA; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TMRM: tetramethylrhodamine, methyl ester, perchlorate; ULK1: unc-51 like autophagy activating kinase 1; ULK2: unc-51 like autophagy activating kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; v-ATPase: vacuolar-type H+-translocating ATPase; WT: wild-type.

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Authors+Show Affiliations

Fernandez-Mosquera L
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany. b Doctoral Program in Molecular Medicine, Georg August University Goettingen , Goettingen , Germany.
Yambire KF
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany. c International Max-Planck Research School in Neuroscience , Goettingen , Germany. d European Neuroscience Institute Goettingen, University Medical Center Goettingen and Max-Planck Society , Goettingen , Germany.
Couto R
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany. e Doctoral Program in Molecular Biology of Cells, Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Goettingen , Goettingen , Germany.
Pereyra L
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany. e Doctoral Program in Molecular Biology of Cells, Göttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences, University of Goettingen , Goettingen , Germany.
Pabis K
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany.
Ponsford AH
f Institute of Translational Medicine, University of Liverpool , Liverpool , UK.
Diogo CV
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany.
Stagi M
f Institute of Translational Medicine, University of Liverpool , Liverpool , UK.
Milosevic I
d European Neuroscience Institute Goettingen, University Medical Center Goettingen and Max-Planck Society , Goettingen , Germany.
Raimundo N
a Institute of Cellular Biochemistry, University Medical Center Goettingen , Goettingen , Germany.

MeSH

AMP-Activated Protein KinasesAnimalsAutophagosomesCalciumCell DeathElectron Transport Complex IFibroblastsHEK293 CellsHeLa CellsHumansLysosomesMiceMitochondriaMitochondrial DiseasesPhosphatidylinositol 3-KinasesPhosphatidylinositol PhosphatesProto-Oncogene ProteinsTransient Receptor Potential ChannelsTumor Suppressor Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30917721

Citation

Fernandez-Mosquera, Lorena, et al. "Mitochondrial Respiratory Chain Deficiency Inhibits Lysosomal Hydrolysis." Autophagy, vol. 15, no. 9, 2019, pp. 1572-1591.
Fernandez-Mosquera L, Yambire KF, Couto R, et al. Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis. Autophagy. 2019;15(9):1572-1591.
Fernandez-Mosquera, L., Yambire, K. F., Couto, R., Pereyra, L., Pabis, K., Ponsford, A. H., Diogo, C. V., Stagi, M., Milosevic, I., & Raimundo, N. (2019). Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis. Autophagy, 15(9), 1572-1591. https://doi.org/10.1080/15548627.2019.1586256
Fernandez-Mosquera L, et al. Mitochondrial Respiratory Chain Deficiency Inhibits Lysosomal Hydrolysis. Autophagy. 2019;15(9):1572-1591. PubMed PMID: 30917721.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitochondrial respiratory chain deficiency inhibits lysosomal hydrolysis. AU - Fernandez-Mosquera,Lorena, AU - Yambire,King Faisal, AU - Couto,Renata, AU - Pereyra,Leonardo, AU - Pabis,Kamil, AU - Ponsford,Amy H, AU - Diogo,Cátia V, AU - Stagi,Massimiliano, AU - Milosevic,Ira, AU - Raimundo,Nuno, Y1 - 2019/03/27/ PY - 2019/3/29/pubmed PY - 2020/7/7/medline PY - 2019/3/29/entrez KW - AMPK KW - MCOLN1 KW - calcium KW - lysosomal Ca KW - lysosomes KW - mitochondria KW - mitochondrial respiratory chain deficiency SP - 1572 EP - 1591 JF - Autophagy JO - Autophagy VL - 15 IS - 9 N2 - Mitochondria are key organelles for cellular metabolism, and regulate several processes including cell death and macroautophagy/autophagy. Here, we show that mitochondrial respiratory chain (RC) deficiency deactivates AMP-activated protein kinase (AMPK, a key regulator of energy homeostasis) signaling in tissue and in cultured cells. The deactivation of AMPK in RC-deficiency is due to increased expression of the AMPK-inhibiting protein FLCN (folliculin). AMPK is found to be necessary for basal lysosomal function, and AMPK deactivation in RC-deficiency inhibits lysosomal function by decreasing the activity of the lysosomal Ca2+ channel MCOLN1 (mucolipin 1). MCOLN1 is regulated by phosphoinositide kinase PIKFYVE and its product PtdIns(3,5)P2, which is also decreased in RC-deficiency. Notably, reactivation of AMPK, in a PIKFYVE-dependent manner, or of MCOLN1 in RC-deficient cells, restores lysosomal hydrolytic capacity. Building on these data and the literature, we propose that downregulation of the AMPK-PIKFYVE-PtdIns(3,5)P2-MCOLN1 pathway causes lysosomal Ca2+ accumulation and impaired lysosomal catabolism. Besides unveiling a novel role of AMPK in lysosomal function, this study points to the mechanism that links mitochondrial malfunction to impaired lysosomal catabolism, underscoring the importance of AMPK and the complexity of organelle cross-talk in the regulation of cellular homeostasis. Abbreviation: ΔΨm: mitochondrial transmembrane potential; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; ATP: adenosine triphosphate; ATP6V0A1: ATPase, H+ transporting, lysosomal, V0 subbunit A1; ATP6V1A: ATPase, H+ transporting, lysosomal, V0 subbunit A; BSA: bovine serum albumin; CCCP: carbonyl cyanide-m-chlorophenylhydrazone; CREB1: cAMP response element binding protein 1; CTSD: cathepsin D; CTSF: cathepsin F; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethyl sulfoxide; EBSS: Earl's balanced salt solution; ER: endoplasmic reticulum; FBS: fetal bovine serum; FCCP: carbonyl cyanide-p-trifluoromethoxyphenolhydrazone; GFP: green fluorescent protein; GPN: glycyl-L-phenylalanine 2-naphthylamide; LAMP1: lysosomal associated membrane protein 1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryonic fibroblast; MITF: melanocyte inducing transcription factor; ML1N*2-GFP: probe used to detect PtdIns(3,5)P2 based on the transmembrane domain of MCOLN1; MTORC1: mechanistic target of rapamycin kinase complex 1; NDUFS4: NADH:ubiquinone oxidoreductase subunit S4; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; pcDNA: plasmid cytomegalovirus promoter DNA; PCR: polymerase chain reaction; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns(3,5)P2: phosphatidylinositol-3,5-bisphosphate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; P/S: penicillin-streptomycin; PVDF: polyvinylidene fluoride; qPCR: quantitative real time polymerase chain reaction; RFP: red fluorescent protein; RNA: ribonucleic acid; SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis; shRNA: short hairpin RNA; siRNA: small interfering RNA; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; TMRM: tetramethylrhodamine, methyl ester, perchlorate; ULK1: unc-51 like autophagy activating kinase 1; ULK2: unc-51 like autophagy activating kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1; v-ATPase: vacuolar-type H+-translocating ATPase; WT: wild-type. SN - 1554-8635 UR - https://www.unboundmedicine.com/medline/citation/30917721/Mitochondrial_respiratory_chain_deficiency_inhibits_lysosomal_hydrolysis_ DB - PRIME DP - Unbound Medicine ER -