Organelles in Disease 185

Acknowledgements
Contents
Golgi pH and Ion Homeostasis in Health and Disease
1 Introduction
2 Maintenance of Golgi pH Homeostasis
2.1 Golgi Acidification by the V-ATPase
2.2 Counter Ion Transport
2.3 Proton Leakage Pathway
2.4 Golgi Homeostasis of Other Ions
3 Diseases Associated with Altered Golgi pH and Ion Homeostasis
3.1 Autosomal Recessive Cutis Laxa Type II
3.2 Cancers
3.3 Viral Infections
3.4 Multigenerational Non-syndromic Intellectual Disability (ID)
3.5 Angelman Syndrome and Autism Spectrum Disorders
3.6 Hailey-Hailey Disease
3.7 Congenital Disorder of Glycosylation 2K (CDG2K)
3.8 Menkes Disease and Related Syndromes
4 Perspectives and Key Questions
References
Stress Granules in Cancer
1 Introduction
2 Properties of Stress Granules
2.1 Formation of Stress Granules
2.2 Stress Granule Structure
3 Dysregulated Cancer Signaling and Stress Granule Formation
3.1 RAS
3.2 mTORC1
3.3 Glycolysis and the Hexosamine Biosynthetic Pathway
3.4 HDAC6
4 Stress Granules and Cancer Hallmarks
4.1 Stress Granules and Proliferation
4.2 Stress Granules and Suppression of Cell Death
4.2.1 Stress Granule-Mediated Suppression of Stress-Induced Apoptosis
4.2.2 Stress Granules and Chemotherapy Resistance
4.3 Stress Granules and Tumor Metastasis
5 Concluding Remarks
References
Lipid Droplets in Cancer
1 Introduction
2 Lipid Droplets Are Dynamic Organelles
2.1 Lipid Droplets Are Versatile Ensembles of Lipids and Proteins
2.2 Lipid Droplet Biogenesis Occurs at the Crossroads of Membrane and Neutral Lipid Metabolism
2.3 Lipid Droplet Breakdown Occurs via Lipolysis or Lipophagy
3 Lipid Droplets Are at the Core of Cancer Metabolic Reprogramming
3.1 Cancer Cells Use Ingenious Ways of Lipid Acquisition That Converge at the Lipid Droplet
3.2 Lipid Droplets and Nutrient Scavenging
3.3 Lipid Droplets Maintain Membrane Unsaturation During Stress
3.4 Lipid Droplets Match Nutrient Fluctuations with Cell Growth and Survival
3.4.1 Lipid Droplets Are Rapidly Mobilizable Energy Sources During Stress
3.4.2 Cancer Cells Depend on the Long-Term Supply of Lipid Droplet-Derived Lipids
3.4.3 Devouring and Creating Fat: Metabolic Flexibility Driving Tumorigenesis
3.5 When the Going Gets Tough, Lipid Droplets Team Up with Autophagy
3.6 Lipid Droplets, Lipid Peroxidation, and Ferroptosis in Cancer
4 Conclusions and Perspectives
References
Patterns of Ciliation and Ciliary Signaling in Cancer
1 Introduction
2 Ciliation and Cancer Cells
3 Ciliation in the Tumor Microenvironment
4 Targeted Cancer Therapies and Cilia
5 Cilia, Ectosomes, and Exosomes
6 Summary
References
Targeting Cancer Lysosomes with Good Old Cationic Amphiphilic Drugs
1 Introduction
2 Lysosomal Functions: Beyond Nutrient Recycling
2.1 Recycling Centers with Acid Hydrolyses as Workhorses
2.2 Metabolic Adaptation Governed by the LAMTOR Complex
2.3 Position Matters: Plasma Membrane Repair and Exocytosis
2.4 Lysosomal Membrane Permeabilization: More Than a Cell Suicide Mechanism
2.4.1 Lysosome-Dependent Cell Death
2.4.2 Lysosomal Leakage as an Intracellular Delivery System
2.4.3 Maintenance of Lysosomal Membrane Integrity
3 Metastatic Cancer: A Lysosomal Disease
3.1 How Do Proliferating Cells Maintain Lysosomal Biogenesis?
3.2 Specific Upregulation of Cysteine Cathepsins
3.3 Peripheral Lysosomes: Drivers of Metastatic Behavior and Cell Survival
3.4 Lysosomal Control of pH Gradient Reversal
3.5 Multidrug Resistance: Lysosomal Sequestration of Chemotherapeutics
3.6 Control of Lysosomal Membrane Integrity in Cancer Cells
4 Lysosomes as Targets for Cancer Therapy
4.1 Clinically Relevant Inducers of Lysosomal Membrane Permeabilization
5 Targeting Cancer Lysosomes by SMPD1-Inhibiting CADs
5.1 Chemical Characteristics of CADs and SMPD1-Inhibiting CADs
5.2 CAD-Induced Lysosome-Dependent Cell Death
5.3 Multiple Anti-cancer Activities of CADs
5.3.1 Consequences of Increased Lysosomal pH
5.3.2 Consequences of SMPD1 Inhibition
5.4 Potential of CADs as Anti-cancer Agents
6 Perspectives
References
Cancer-Related Increases and Decreases in Calcium Signaling at the Endoplasmic Reticulum-Mitochondria Interface (MAMs)
1 Introduction
2 MAM-Localized Ca2+ Signaling Modulators in Cancer: Channels and Receptors
2.1 ER Side
2.2 Mitochondrial Side
3 Decrease in ER-Mitochondria Ca2+ Crosstalk
3.1 Dysfunctional ER-Ca2+ Release
3.2 Perturbed Mitochondrial Ca2+ Uptake
4 Upregulation of ER-Mitochondria Ca2+ Crosstalk
4.1 New Insights into Ca2+ Signaling Perturbation in the MAMs
4.2 Increased ER-Ca2+ Release
4.3 Increased Mitochondrial Ca2+ Uptake
5 Conclusions
References
Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases
1 A Balancing Act: pH Regulation in the Endosome
2 Lessons from Baker´s Yeast
3 Endosomopathy Is a Preclinical Hallmark of Alzheimer´s Disease
4 Protons to Patients: Linking Endosomal pH and Neurodegeneration
5 Acid Indigestion in the Endosome: The Role of ApoE4
6 NHE6 Is an ApoE4 Effector
6.1 NHE6 Is Downregulated in Alzheimer´s Disease
6.2 Co-expression Clues in Alzheimer´s Disease
6.3 NHE6 Blocks Amyloid Buildup
6.4 NHE6 Promotes Amyloid Clearance
6.5 The Goldilocks Scenario: Just the Right pH?
7 Big Data Could Fuel Big Progress
8 Extending the Endosomal Acid-Base Paradigm Beyond Alzheimer´s Disease
9 Summary, Key Questions, and Translational Prospects
References
Endolysosomal Disorders Affecting the Proximal Tubule of the Kidney: New Mechanistic Insights and Therapeutics
1 Introduction
2 Endolysosomal System and the Kidney Proximal Tubule
3 Diseases Targeting the Kidney Proximal Tubule
4 Inherited Endolysosomal Disorders Causing Proximal Tubule Dysfunction
4.1 Dent Disease and Lowe Syndrome
4.2 Cystinosis
5 Current Treatments and Potential Therapeutics
6 Conclusions
References
Endo-Lysosomal Cation Channels and Infectious Diseases
1 Introduction
2 Examples of Pathogens Hijacking the Endo-Lysosomal System
2.1 Viruses
2.2 Bacteria and Bacterial Toxins
3 Endo-Lysosomal Cation Channels in Pathogen Uptake, Trafficking, and Replication
3.1 Two-Pore Channels: TPCs
3.2 Mucolipins: TRPMLs
4 Summary
References