Mechanisms of Cell Injury: Loss of Calcium Homeostasis

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1 Mechanisms of Cell Injury: Loss of Calcium Homeostasis SCPA610: Cellular Pathology Amornrat N. Jensen, Ph.D.

2 Leading questions Why is intracellular calcium important for the cell? How does the cell regulate intracellular calcium levels?

3 Calcium (Ca 2+ ): important cellular messenger Regulate various cellular functions including cell growth and differentiation Image modified from Berridge MJ, et al. Nature Review, 2003

4 Cytosolic calcium concentration is relatively low Cytosolic calcium is usually in nanomolar range, except during a calcium signal event Na + /Ca 2+ exchanger Plasma membrane Ca 2+ -ATPase Extracellular calcium is in millimolar range Ca 2+ uniporter The level of free intracellular calcium is regulated through the action of a number of binding proteins and pumps/ exchangers Sarco(endo)plasmic reticulum Ca 2+ -ATPase

5 Activation of calcium signaling Image from Berridge MJ, et al. Nature Reviews, 2000

6 Downstream effects of calcium signaling Different types of cell contain different sets of calcium signals to control their functions Image modified from Berridge MJ, et al. Nature Reviews, 2000

7 Calcium- signaling toolkit fine-tunes Ca 2+ signaling Berridge MJ, et al. Nature Molecular Cell Biology Reviews

8 Ca 2+ signal transduction is based on rises in free cytosolic Ca 2+ concentration Increased free cytosolic calcium can emerge from: 1. Extracellular space 2. Released calcium from intracellular stores - ER, Golgi, mitochondria, nuclear envelope, and lysosomes Popi Syntichaki & Nektarios Tavernarakis, Nature Reviews Neuroscience, 2003

9 ER serves as the major internal calcium reservoir Sequestration of calcium into the ER is mediated by the sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) ER calcium release is controlled by ryanodine (RyR), and inositol trisphosphate receptors (IP 3 R) Within the ER, calcium binds to molecular chaperones such as calreticulin and calnexin

10 Release of ER calcium Triggered by various messengers in response to stimuli: - inositol-1,4,5-triphosphate - cyclic ADP ribose (cadpr) - nicotinic acid dinucleotide phosphate (NAAP) - sphingosine-1-phosphate (S1P) Berridge MJ, et al. Nature Molecular Cell Biology Reviews

11 Example: lymphocyte proliferation triggered by calcium signaling TCR: T-cell Receptor Image from Berridge MJ, et al. Nature Reviews, 2000

12 Loss of calcium homeostasis Often from persistent increased cytoplasmic calcium levels (physiological changes of Ca 2+ are usually rapid and do not last long) Pathology can be reversible or irreversible depending on cell types and the intensities of calcium toxicity Image from Berridge MJ, et al. Nature Reviews, 2000

13 Effects of increased cytosolic calcium levels Activation of various enzymes Opening of mitochondrial permeability transition pore (MPTP)

14 Perturbation of mitochondrial Ca 2+ plays a critical role in Ca 2+ cytotoxicity Opening of MPTP leads to uncouples of oxidative phosphorylation and reduction of ATP levels Image from

15 Stimuli triggering high cytosolic calcium Membrane damage Ischemia Toxic agents/ drugs - methylmercury, acetaminophen

16 Calcium depletion can also induce cell injury Depletion of calcium from the ER results in a cellular stress condition termed ER stress

17 Robbins Basic Pathology, 9th Ed Signaling pathways activating a caspase cascade

18 Functions of ER Protein synthesis Calcium storage Biosynthesis of lipid and sterols Protein folding Post-translational modifications and disulfide bond formation

19 Correct folding of proteins is facilitated by molecular chaperones in the ER Calcium-dependent chaperone proteins

20 Folding of protein in the ER

21 ER stress ER stress occurs when there is an imbalance between protein-folding load and folding capacity of the ER

22 Causes of ER stress Disturbances of calcium homeostasis Calcium-dependent molecular chaperones Viral infection Overload the ER with viral protein synthesis Alterations in cellular redox regulation Interfere with disulfide boding in the ER lumen Glucose deprivation Thought to interfere with N-linked glycosylation in the ER

23 Major responses to ER stress ER associated degradation (ERAD) Unfolded protein response (UPR) Induction of apoptosis Ma Y. and Hendershot L.M. Nature Reviews Cancer, 2004

24 IRE1 (inositol-requiring kinase 1) UPR signaling cascades Initiated by three ER-localized protein sensors PERK (Protein kinase RNA -like ER kinase) ATF6 (activating transcription factor 6) Modified from Zhang and Kaufman, Nature, 2008

25 IRE1 PERK ATF6 ERAD Protein folding Lipid synthesis Cellular stress response Modified from Hetz, Nature Reviews Molecular Cell Biology, 2012

26 UPR triggers apoptosis under prolong ER stress

27 UPR triggers apoptosis under prolong ER stress UPR-mediated cell death is thought to contribute to the pathogenesis of many diseases Hetz, Nature Reviews Molecular Cell Biology, 2012

28 Human diseases linked to ER stress Ozcan and Tabas, Annu Rev Med., 2012

29 Calcium signaling and disease Hailey-Hailey disease and Darier disease - Skin diseases caused by mutations of a new family of Golgi/secretory pathway calcium/manganese ATPases (SPCA) - Characterized by persistent blisters and erosions of the skin Image from Wikipedia

30 Calcium signaling and disease Skeletal-muscle pathology caused by Abnormal ryanodine receptors Malignant hyperthermia, porcine stress syndrome, central core disease Defects in plasma membrane voltage-gated Ca 2+ channels Hypokalemic periodic paralysis Mutations in SERCA Brody disease - muscle cramping and stiffening after exercise

31 Calcium signaling and disease Neurologic disorders associated with defect in molecules involved in calcium signaling Plasma-membrane Ca 2+ channels Episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, glutamate excitotoxicity IP3 receptors Lowe s oculocerebrorenal syndrome, manic depression, Alzheimer s disease

32 Calcium- signaling toolkit fine-tunes Ca 2+ signaling Berridge MJ, et al. Nature Molecular Cell Biology Reviews

33 References Calcium signaling toolkits (interactive) Dong et al., Annu. Rev. Pathol. Mech. Dis. 2006, Calcium in cell injury and death. Berridge et al., Nature Reviews. 2000, The versatility and universality of calcium signaling Sammels et al. Cell Calcium. 2010, Intracellular Ca2+ storage in health and disease: A dynamic equilibrium