Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C
Abstract
:1. Introduction
2. Materials and Methods
2.1. Neural Differentiation
2.2. Live Cell Staining and Imaging
2.3. Analysis of Organelle Transport
- -
- Track duration: time between the first and the last spot of a track;
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- Mean speed: mean speed over the time course of track;
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- Maximal speed: maximal speed between two spots of a track;
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- Minimal speed: minimal speed between two spots of a track;
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- Median speed: median of all velocities between two spots;
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- Track displacement/track length: distance between the first and last spot of a track;
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- Total distance travelled: sum of all distances between two consecutive spots;
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- Maximal distance travelled: furthest distance from the starting point of a track;
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- Confinement ratio:
- Z(PXMut) = Z-Score of parameter x (e.g., mean speed) of the NPC1-deficient cell line (Mut) compared to the control cell line (ctrl). PXMut = mean of parameter X of the NPC1-deficient cell line;
- PXCtrl = mean of parameter X of the control cell line;
- SDXMut = standard deviation of parameter X of the NPC1-deficient cell line;
- SDXCtrl = standard deviation of parameter X of the control cell line;
- NXMut = sample size of parameter X of the NPC1-deficient cell line;
- NXCtrl = sample size of parameter X of the control cell line.
2.4. Immunofluorescence and Fluorescence Microscopy
2.5. Colocalization Analysis
2.6. Determination of Mitochondrial Morphology
2.7. Western Blot Analysis
2.8. Analysis of Mitochondrial Membrane Potential
2.9. Statistical Analysis
3. Results
3.1. Mitochondria Were Smaller, but Showed No Differences in Function
3.2. The Transport Speed of Moving Mitochondria was Reduced Due to an Increased Amount of Stops
3.3. Degradation of Mitochondria via Mitophagy Is Reduced
3.4. Initiation and Progression of Autophagy Was Affected
3.5. Lysosomes but Not Autophagosomes Showed a Tendency of a Reduced Transport
4. Discussion
4.1. Analysis of Mitochondrial Morphology and Function
4.2. Impact of Hampered Mitochondrial Transport on Mitophagy in NP-C1- and NP-C2-Deficient Cells
4.3. Impairement of Autophagy in NPC1- and NPC2-Deficient Cells
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
ALS | Amyotrophic lateral sclerosis |
ATG4 | Autophagy-related protein 4 |
ATP | Adenosine triphosphate |
AVs | Autophagic vesicles |
BafA1 | Bafilomycin A1 |
BSA | Bovine serum albumin |
CCCP | Carbonyl cyanide 3-chlorophenylhydrazone |
DMEM | Dulbecco’s Modified Eagle’s Medium |
DMSO | Dimethyl sulfoxide |
EGF | Epidermal growth factor |
FGF2 | Basic fibroblast growth factor |
GAPDH | Glyceraldehyde-3-phosphate dehydrogenase |
GFP | Green-fluorescent protein |
HD | Huntington’s disease |
Hsp60 | Heat-shock protein 60 |
iPSC | Induced pluripotent stem cell |
Lamp2 | Lysosome-associated membrane protein 2 |
LBPA | Lysobisphosphatidic acid |
LC3BI/II | Microtubule-associated proteins 1A/1B light chain 3B |
LRRK2 | Leucine-rich repeat kinase 2 |
LSM | Laser scanning microscope |
mGluR5 | Group I metabotropic glutamate receptor 5 |
Miro1/2 | Mitochondrial rho GTPase 1 or 2 |
MLN64 | Metastatic lymph node 64 protein |
MMP | Mitochondrial membrane potential |
mTORC1 | Mammalian target of rapamycin complex 1 |
NDCs | Neuronal differentiated cells |
NF-L | Neurofilament light chain |
NP-C 1/2 | Niemann–Pick disease type C 1/2 |
NPCs | Neural progenitor cells |
Nrf2 | Nuclear factor erythroid 2-related factor 2 |
OPTN | Optineurin |
PBS | Phosphate-buffered saline |
PD | Parkinson’s disease |
PFA | Paraformaldehyde |
PGC-1α | Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha |
PINK1 | Serine/threonine kinase PTEN-induced kinase 1 |
PSA-NCAM | Polysialylated-neural cell adhesion molecule |
RFP | Red-fluorescent protein |
ROS | Reactive oxygen species |
SCAR20 | Spinocerebellar ataxia 20 |
SNARE | Soluble N-ethylmaleimide-sensitive-factor attachment receptors |
SQSTM1/p62 | Sequestosome-1 |
SNX14 | Sorting nexin 14 |
TBK1 | TANK-binding kinase 1 |
Tom20 | Mitochondrial import receptor subunit TOM20 homolog |
ULK-1 | mTOR/Unc-51-like kinase |
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Liedtke, M.; Völkner, C.; Hermann, A.; Frech, M.J. Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C. Cells 2022, 11, 507. https://doi.org/10.3390/cells11030507
Liedtke M, Völkner C, Hermann A, Frech MJ. Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C. Cells. 2022; 11(3):507. https://doi.org/10.3390/cells11030507
Chicago/Turabian StyleLiedtke, Maik, Christin Völkner, Andreas Hermann, and Moritz J. Frech. 2022. "Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C" Cells 11, no. 3: 507. https://doi.org/10.3390/cells11030507
APA StyleLiedtke, M., Völkner, C., Hermann, A., & Frech, M. J. (2022). Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C. Cells, 11(3), 507. https://doi.org/10.3390/cells11030507