Structure. Lysosomes are membrane-enclosed organelles. Hydrolytic enzymes. Variable in size & shape need

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1 Lysosomes

2 Structure Lysosomes are membrane-enclosed organelles Hydrolytic enzymes Variable in size & shape need Degrade material taken up from outside and inside the cell Variable in size and shape

3 Lysosomal enzymes ~50 different acid hydrolases The enzymes are active at the acidic ph (about 5) that is maintained within lysosomes Levels of Protection: Compartmentalization Inactive if released A proton pump maintains lysosomal ph

4 Lysosomal storage diseases Glycolipidoses (sphingolipidoses) Oligosaccharidoses Mucopolysaccharidoses: deficiencies in lysosomal hydrolases of glycosaminoglycans (heparan, keratan and dermatan sulfates, chondroitin sulfates). They are chronic progressively debilitating disorders that lead to severe psychomotor retardation and premature death

5 Sphingolipids Glucocerebroside Glucocerebroside is a glycosphingolipid (a monosaccharide attached directly to a ceramide unit (a lipid) It is a byproduct of the normal recycling of red blood cells which are phagocytosed by macrophages, degraded and their contents recycled to make new cells.

6 Glycolipidosis Gaucher s disease Most common, common in Jews Size, quantity & foamy appearance 3 types according to severity Type I: (least severe, most common) the nervous system is not involved; spleen and liver enlargement, development of bone lesions Types II and III (more severe, much rarer): only macrophages Phagocytosis: ingesting large amounts of lipids to be degraded in lysosomes

7 Gaucher disease (acid glucocerebrosidase deficiency) Mutation in acid-β glucosidase (glucocerebrosidase) gene, which catalyzes the hydrolysis of glucocerebroside to glucose & ceramide

8 Carbohydrate metabolism

9 Oligosaccharidoses No. Type Defective enzyme Organ affected Glycogen in the affected organ Clinical features 0 glycogen synthase-2 Liver hypoglycemia, early death, hyperketonia I Von Gierke disease Glucose 6-phosphatase or transport system Liver and kidney Increased amount; normal structure. Massive enlargement of the liver. Failure to thrive. Severe hypoglycemia, ketosis, hyperuricemia, hyperlipemia. II Pompe disease -1,4-Glucosidase All organs Massive increase in amount; Cardiorespiratory failure causes death, usually before age 2. (lysosomal) normal structure. III Cori disease Amylo-1,6-glucosidase Muscle and liver Increased amount; short outer Like type I, but milder course. (debranching enzyme) branches. IV Andersen disease Branching enzyme Liver and spleen Normal amount; very long outer branches. Progressive cirrhosis of the liver. Liver failure causes death, usually before age 2. V McArdle disease Phosphorylase Muscle Moderately increased amount; normal structure. Limited ability to perform strenuous exercise because of painful muscle cramps. Otherwise patient is normal and well developed. VI Hers disease Phosphorylase Liver Increased amount. Like type I, but milder course. VII Tarui Disease Phosphofructokinase Muscle Increased amount; normal structure. VIII Phosphorylase kinase Liver Increased amount; normal structure. IX phosphorylase kinase, β- liver, leukocytes, subunit muscle Fanconi-Bickel, hepatorenal glycogenosis glucose transporter-2 (GLUTliver 2) failure to thrive, hepatomegaly, rickets, proximal renal tubular dysfunction Like type V. Mild liver enlargement. Mild hypoglycemia. like VI

10 Pompe disease Lysosomes become engorged with glycogen because they lack α-1,4-glucosidase, a hydrolytic enzyme confined to these organelles Glycogen structure is normal, but its amount is excessive

11 I-cell disease (mucolipidosis II) N-Acetylglucosamine-1-Phosphotransferase Deficiency Lack of targeting of lysosomal enzymes from Golgi A deficiency in tagging enzyme Features: severe psychomotor retardation that rapidly progresses leading to death between 5 and 8 years of age.

12 Treatment

13 Chloroquine Anti-malarial agent In the parasite s vaculoe, hemoglobin is digested and heme is modified by heme polymerase If heme is not modified, it is toxic to the parasite Chloroquine inhibits the enzyme It is a weak base that becomes protonated at acidic ph It crosses membranes into the malarial digestive vacuole

14 Endocytosis Extracellular: endocytic vesicles fuse with early endosomes Membrane receptors are recycled via recycling endosomes Early endosomes mature into late endosomes Recycling endosomes Intracellular: Transport vesicles from Golgi fuse with late endosomes, Late endosomes mature into lysosomes Receptors are recycled to the Golgi Maturation Maturation or fusion

15 Phagocytosis & autophagy

16 Mitochondria & Peroxisomes

17 What are the mitochondria? Mitochondria are thought to have evolved from bacteria via endosymbiosis Most mitochondrial proteins are translated on free cytosolic ribosomes and imported into the organelle They contain their own DNA, which encodes trnas, rrnas, and some mitochondrial proteins Mitochondrial proteins are encoded by their own genomes and nuclear genome

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19 Structure Outer membrane Permeable, porins, ~5000 Da Inner membrane Impermeable Mainly proteins ( 75%) Forms folds (cristae) to increase surface area Function; OxPhos, transport of metabolites Intermembrane space Composition is similar to the cytosol Matrix Contains mitochondrial genetic system and the enzymes responsible for the Krebs cycle

20 Properties and features They are located in cells requiring high-energy use such as synapses They are dynamic (fusion & division) Exchange genetic material Regulate autophagy Cell survival

21 The Genetic System of Mitochondria Mitochondrial DNA (~16 Kb) is circular and present in multiple copies per organelle It encodes 13 proteins involved in electron transport and oxidative phosphorylation, two rrnas, and 22 trnas.