Cell Mitochondria: Function and Dysfunction: Examples of Their Disorders and Their Management - PowerPoint Presentation

1. Cell Mitochondria: Function and Dysfunction: Examples of Their Disorders and Their ManagementPHM 142-Unit 8October 27, 2022Dr. Fawwaz Al-Joudi1

2. Shapes and Sizes of Mitochondria

3. Mitochondrial Fission and fusionThe upper sequence of pictures is showing 3 frames of mitochondria fusing together, whereas the lower 3 picture frames are showing one mitochondrion splitting into two and moving apart.The middle EM photo shows a mitochondrion (purple) being encircled by endoplasmic reticulum (ER) tubules marking sites of future fusion.The lower diagram is showing the ER tubules encircling a mitochondrion which undergoes fission. (Drp1 is a member of the dynamin family of proteins involved in severing membrane structures).

4. Mitochondria and OxygenIf a cell is deprived of oxygen, such as during overly strenuous physical activity or if there is significant blockage of an artery, then the TCA cycle doesn't function efficiently and pyruvate is converted to lactic acid or lactate.

5. Mitochondrial dysfunctionMitochondrial adverse effects are generally systemic, though the effects could often be cell type-specific, as is the case in many known mitochondrial diseases, where a mutation (s) results in a pathology in only one or a few tissues.5

6. Overview of the consequences of erroneous ROS production in mitochondriaROS production within mitochondria can lead to oxidative damage to mitochondrial proteins, membranes, and mtDNA. Mitochondrial oxidative damage leads to the release of cytochrome c (cyt c) into the cytosol resulting in cell apoptosis. Increased permeability makes the inner membrane permeable to small molecules. Mitochondrial ROS are also important in cell signalling pathways which modulate several cellular functions.Galley et al., BJ Anaesthesia, 2011.

7. Production of Reactive Nitrogen SpeciesThe mitochondrial respiratory chain can produce nitric oxide, which itself has an unpaired electron and is therefore a free radical, and other nitric oxide by-products called reactive nitrogen species (RNS). The highly toxic molecule peroxynitrite is formed from the reaction of nitric oxide with superoxide anion.RNS can have detrimental effects through oxidation, nitrosylation, or nitration of various cellular targets, including proteins, nucleic acids, and endogenous antioxidants such as glutathione.

8. Reactive oxygen species are required in:

9. Range of diseases that can result from abnormal mitochondrial function In most cases, mitochondrial diseases are characterized by degeneration of muscle or brain tissue, both of which utilize exceptionally large amounts of ATP.

10. Patients with serious conditions in musclesSuch

11. Muscle biopsy: mitochondrial abnormalitiesMitochondrial abnormality in muscle visualised with Gomori stain, degenerating muscle fibers showing accumulations of red staining “blotches” just beneath the plasma membranes of cells, which are due to abnormal proliferation of mitochondria.

12. Mitochondrial Electron MicrographsElectron micrograph showing crystalline structures within the mitochondrial matrix from cells of a patient with abnormal mitochondria.

13. Mutant Mitochondrial DNA can vary within an individual

14. Disorders with Mitochondrial DysfunctionPrimary mitochondrial disease (PMD): genetically inherited mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that directly affect mitochondrial metabolism (i.e. with direct effects on oxidative phosphorylation). Secondary mitochondrial dysfunction: Mitochondrial dysfunction is also seen in a number of different genetic disorders. These are not strictly mitochondrial diseases.The mutations generally affect the function of the mitochondrion, compromising, among other processes, the production of cellular adenosine triphosphate (ATP).14

15. So, now, we will be sailing around the following topics:How mitochondria and mitochondria-associated disorders are inherited.Genetic Disorders with mitochondrial dysfunction and their medical therapies.General Mitochondria replacement therapy.Some other mitochondria-related disorders.Medication-induced mitochondrial damage.Mitochondria and aging.

16. Maternal inheritance of mitochondriaMaternal inheritance is a form of non-Mendelian inheritance in which the mutation and disorder are passed from mothers—never from fathers—to all of their children. In sperms, there are only a few mitochondria and are located in the midpiece. Oocytes have many more mitochondria than do sperms. Moreover, and by unclear mechanisms, the sperm mitochondria disappear after fertilization. So, the oocyte remains the major contributor of mitochondria.

17. Pedigree of Leber

18. Localization of mitochondria in the mid piece surrounding the proximal portion of the flagellum of a bat sperm

19. Mitochondria and pathogenesis to the nervous systemWith their high sensitivity to reduced blood flow, brain mitochondria exhibit the first signs

20. Mitochondria and Neurodegeneration A substantial evidence points at the role of mitochondria in neurodegeneration which is based on the vicious cycle of mitochondrial DNA mutations, bioenergetic decline and free radical damage.

21. Disorders with mitochondrial dysfunctionMain disorders:Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).Leber’s Hereditary Optic Neuropathy (LHON).Leigh syndrome.The Kearns-Sayre syndrome. Myoclonus Epilepsy with Ragged-Red Fibers (MERRF).Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). neuropathy, ataxia, and retinitis pigmentosa, also known as NARP syndrome.Alpers disease.21

22. mtDNA: mutations and disease-correlations

23. MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)The other synonym name is: Myopathy, Mitochondrial-Encephalopathy-Lactic Acidosis-StrokeThis is a rare disorder that begins in childhood, usually between two and fifteen years of age, and mostly affects the nervous system and muscles.

24. MELAS: symptomsThe most common early symptoms are seizures, recurrent headaches, loss of appetite and recurrent vomiting. Stroke-like episodes with temporary muscle weakness on one side of the body (hemiparesis) may also occur and this can lead to altered consciousness, vision and hearing loss, loss of motor skills and intellectual disability.

25. MELAS: affected populationMELAS syndrome is a rare disorder that affects males and females in equal numbers. Although rare, MELAS syndrome is probably the most common type of mitochondrial myopathy caused by mutations in mtDNA.

26. MELAS etiology: mtDNA mutationsMutations in the A3243G pathogenic variant in the mtDNA gene MT-TL1 (a tRNA gene), are associated with MELAS in approximately 80% of cases. Other mutations: MT-TQ, MT-TH, MT-TK, MT-TS1, MT-ND1, MT-ND5, MT-ND6, and MT-TS2, have also been associated with MELAS syndrome.Some cases of MELAS syndrome appear to occur as the result of a new spontaneous mutation in a mitochondrial gene and are not inherited.In addition, mutations in a nuclear gene (POLG1) were associated with MELAS syndrome in one case.

27. mtDNA: mutations and disease-correlations

28. MELAS: mtDNA genes and tRNA

29. MELAS: other diagnostic featuresLactate and pyruvate both in blood and CSFRagged red fibers in stained muscle biopsyBrain injury (pathology) as observable by MRI Genetic testing to detect mutations in mtDNA29

30. MELAS: Standard TherapiesNo specific treatment is available for MELAS syndrome.Mostly, it is symptomatic treatment:Anti-convulsant drugs (e.g. lamotrigine) to help prevent and control seizures associated with MELAS (n.b. Valproic acid should not be used as an anticonvulsant). Cochlear implants to treat sensorineural deafness.30

31. MELAS: standard therapiesTherapies are sometimes used to increase energy production by the mitochondria and slow the effects of the condition: Coenzyme Q10 and L-carnitine have been beneficial in some patients. Others include menadione, ascorbic acid, riboflavin, thiamine, nicotinamide, creatine monohydrateIn patients with mitochondrial myopathies in general, moderate treadmill training may result in improvement of aerobic capacity and drop in resting lactate levels. The use of intravenous and oral L-arginine has been reported to improve the symptoms of disease during the acute stroke-like episodes. (n.b. arginine may ameliorate the defective local vasodilatation).Genetic counseling is recommended for affected individuals and their families.

32. Idebenone: trade names and chemical structureIdebenone is an organic compound of the quinone family. It is also promoted commercially as a synthetic analogue of coenzyme Q10 (CoQ10).Idebenone in MELAS is under trials to determine if it has an effect on brain lactate.It works by protecting a wide variety of cells from oxidative damage thereby increasing production of energy by cells.Commercial names: Catena, Raxone, SovrimaChemical formula: C19H30O5

33. Mitochondrial replacement therapy This is a modified form of in vitro

34. Leber hereditary optic neuropathy (LHON)LHON is a maternally inherited disorder of visual loss that occurs at the rate of approximately 1:50,000 people. It affects more males than females.It is often characterized by bilateral, painless, subacute loss of central vision during young adult life. Rare cases may appear in early childhood or late adulthood.Main Pathology: development of optic nerve atrophy.Neurologic abnormalities may rarely occur, such as peripheral neuropathy, postural tremors, nonspecific myopathy, and movement disorders.

35. Etiology of LHON (genetic mutations)LHON is caused by mutations in mitochondrial DNA and they are strictly transmitted by maternal inheritance. The three primary mitochondrial DNA LHON-causing mutations are:mt.3460G>A, mt.11778G>A, and mt.14484T>C, which account for over 90% of LHON patients. The most common LHON-causing mutation is mt.11778G>A. Mutations interfere mostly with Complex I.

36. LHON: DiagnosisLHON is diagnosed based on ophthalmologic findings, which include specialized visual testing.Molecular genetic testing for mitochondrial genes associated with LHON can be used to confirm diagnosis. In most cases, other family members of LHON-affected individuals may also be affected.

37. LHON: standard managementAffected individuals should receive supportive management and treatment through the usage of visual aids, occupational rehabilitation, and local social services. Affected individuals should avoid smoking and excessive alcohol consumption, which generate reactive oxygen species (ROS) producing/ aggravating mitochondrial impairments.Genetic counseling is recommended for patients and their families. However, the key to understanding is that female carriers always transmit the gene and male carriers never do.

38. Major Therapeutic approaches In use are modulating agents of the mitochondrial electron transport chain such as:Idebenone:KH-176: this is a potent intracellular redox modulating agent targeting the ROS which are important in the pathogenesis of disorders of mitochondrial oxidative phosphorylation.), Also, inhibitors of apoptosis such as elamipretide (that appears to reduce the production of ROS and stabilize cardiolipin) and Gene therapy such as bone marrow-derived stem cells.Mitochondrial replacement therapy.

39. Mental and cognitive disorders and mitochondriaIt appears that maintaining mitochondrial health is an important strategy in preventing the slow decline of mental faculties with age.Some positive correlations between mitochondrial dysfunction and the following disorders have been reported:- Alzheimer’s disease.- Parkinson disease.Also related to mitochondria are some non-aging disorders:- attention deficit/ hyperactivity disorder.- depression.- chronic fatigue syndrome/ myalgic encephalomyelitis and fibromyalgia.

40. Alzheimer's disease and Mitochondria

41. Alzheimer‘s: mechanism of action of amyloid beta Amyloid beta alters the proper folding of proteins so that they form neurofibrillary tangles, mostly associate with microtubules, evidence of disrupted neuronal cytoskeleton.Amyloid beta also generates free radicals, damages mitochondrial DNA and impairs cellular bioenergetics.Fig. Alzheimer disease:Upper left: a neurofibrillary tangle, and Neurites around a (senile) plaque (lower right).

42. Alzheimer's disease and bioenergetics

43. Alzheimer’s Disease: pathogenesis A potent free radical called peroxynitride

44. Alzheimer's disease: managementIt has suggested that consuming more than 2000 calories a day can double risk the development of mild cognitive impairment

45. Alzheimer's disease treatmentAChE inhibitors (acetyl cholinesterase inhibitors) as they Compensate for the loss of cholinergic neurons. They offer symptomatic relief by inhibiting acetylcholine (ACh) turnover and restoring their synaptic levels.These drugs may help reduce some symptoms and help control some behavioral symptoms.The main side effects of these drugs include diarrhea, nausea, loss of appetite and sleep disturbances. In people with cardiac conduction disorders, serious side effects may include cardiac arrhythmia.The drugs act to improve communication between nerve cells, by increasing the levels of acetylcholine, which is involved in learning, thinking, and memory processes. Examples of these medications include Razadyne® (galantamine), Exelon® (rivastigmine), and Aricept® (donepezil).

46. Alzheimer's disease treatment A medication known as Namenda® (memantine), an N-methyl D-aspartate (NMDA) antagonist, is prescribed to treat moderate to severe Alzheimer’s disease. Namenda® is believed to work by regulating glutamate, an important brain chemical. When produced in excessive amounts, glutamate may lead to brain cell death. Because NMDA antagonists work differently from cholinesterase inhibitors, the two types of drugs can be prescribed in combination.

47. Parkinson Disease (PD)This is a slowly progressive, neurodegenerative disorder characterized by resting tremor, stiffness (rigidity), slow and decreased movement (bradykinesia), and gait and/or postural instability.Parkinson disease affects about:0.4% of people > 40 yr1% of people ≥ 65 yr10% of people ≥ 80 yrThe mean age at onset is the age of 60 years.It is usually idiopathic.47‘Diseases of the Nervous System' by William Gowers

48. Pathology of Parkinson disease Microscopic examination reveals the loss of depigmented catecholaminogenic neurons. In these regions, with the appearance of single or multiple cytoplasmic eosinophilic, round to elongated inclusions called Lewy bodies.Lewy bodies are composed of fine filaments, densely packed in the core but loose at the rim and they are composed of a synuclein, which is an abundant lipid-binding protein normally associated with synapses.

49. Macroscopic Pathology of Parkinson disease:The typical macroscopic findings are pallor of the substantia nigra:A. Normal substantia nigra.B. Depigmented substantia nigra in idiopathic Parkinson disease.

50. Microscopic Pathology of Parkinson disease:Lewy body in substantia nigra neuron, staining bright pink (arrow).

51. Parkinson disease: pathology There is a reduction in the striatal dopamine content.The severity of the motor syndrome is proportional to the dopamine deficiency, which can, at least in part, be corrected by replacement therapy with L-DOPA, the immediate precursor of dopamine.

52. Genetics of PDFamilial forms of PD with autosomal dominant or autosomal recessive inheritance exist.The first gene to be identified as a cause of autosomal dominant PD is the a synuclein gene

53. Parkinson's disease and mitochondria The neurons in the substantia nigra produce the neurotransmitter dopamine, and the death of these cells depletes dopamine stores, and ultimately leads to muscle rigidity, tremors, and difficulty initiating movement.It has been shown that the substantia nigra is that part of the brain that has the greatest number of mutations in mt DNA, and human evidence reveals that the mitochondria of patients with Parkinson's disease exhibit several deficiencies.Examples of defective genes in PD are: LRRK2 gene, SNCA gene and Parkin gene.

54. Mitochondria and The Defective genes in PDSNCA gene-Encodes the main component of Lewy bodies, α-Synuclein.Mutations in this gene are autosomal dominant.It mediates neurotransmitter release at presynaptic terminals and interact with membranes of various organelles, including mitochondria, so it regulates mitochondrial morphology and biogenesis.LRRK2 gene-Most common cause of familial PD, the mutation of which is autosomal dominant.It encodes Kinase 2, which is a multifunctional protein kinase.LRRK2 has been shown to cause mitochondrial fragmentation, increased proton leak and loss of mitochondrial membrane potential, and defective mitophagy (degradation by lysosomes). Parkin gene-Most common autosomal recessive PD.Encodes cytosolic E3 ubiquitin ligase that targets proteins for signalling or proteasomal degradation.Parkin primarily functions in association with mitochondria; Parkin has diverse functions in maintaining healthy mitochondria by regulating their biogenesis and degradation via mitophagy. 54

55. Inhibition of Complex I Can result in Parkinson’s symptomsSupporting evidence linking mitochondrial dysfunction and sporadic Parkinson’s disease through specific inhibition of Complex I with: Rotenone induces degeneration of subset of nigrostriatal dopaminergic neurons, formation of cytoplasmic inclusions and the development of parkinsonian motor behaviour in animal models. 6-Hydroxydopamine (6-OHDA) is a dopamine analogue that inhibits complexes I and IV to generate PD-like disease in animals which develop impaired motor function following degeneration of neurons and decreased dopamine content in substantia nigra.55

56. Mitochondria and Sporadic Parkinson’s diseaseMPTP (synthetic heroin) (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes the clinical development of progressive and irreversible parkinsonism in young drug addicts.Post-mortem studies displayed degeneration of the substantia nigra without the presence of Lewy bodies.56

57. Parkinson’s disease: therapiesManagement: Physical and occupational therapies.Drug therapies:Levodopa is the most effective medication in Parkinson's disease: it is a natural chemical that passes into the brain and is converted to dopamine.Levodopa is combined with carbidopa (Lodosyn) to protect levodopa from early conversion to dopamine outside the brain. This prevents or lessens side effects such as nausea.57

58. Parkinson disease: locate the defect

59. Parkinson’s disease: Other drugsDopamine agonists to activate dopamine receptors in basal ganglia. These include apomorphine, pramipexole, ropinirole, and rotigotine. Monamine oxidase B (MAO-B) inhibitors prevent the enzyme from breaking down dopamine, causing dopamine to accumulate in surviving nerve cells and reduce the symptoms of PD, and when used with levodopa, prolong the action of each dose. They include selegiline and rasagiline.COMT (catechol-O-methyltransferase) inhibitors- E.g. entacapone, tolcaponeThe drug thus prolong the effects of levodopa by preventing the breakdown of dopamine.  Amantadine is an antiviral drug that reduces symptoms of PD by enhancing the action of dopamine. It can be administered alone or with levodopa. Anticholinergic drugs reduce the acetylcholine activity and can be particularly effective for tremors. These Include trihexyphenidyl, benztropine, and ethopropazine. Adverse effects may include cognitive impairment and dry mouth.59

60. Parkinson Disease: Stem Cell TherapyStem Cell Secretome therapy is a fairly recent development in stem cell research. The treatment may offer minimal risk and immense potential to slow down the disease.This attempts to grow and expand stem cells harvested from the patient's own tissue. The process is anticipated to induce the production of the specific regenerative substances.The same method may be used for other disorders.

61. Drug-induced mitochondrial damage

62. Drugs inducing mitochondrial damage (1)Barbiturates

63. Drugs inducing mitochondrial damage (2)Aspirin and valproic acid can sequester coenzyme A.Yet, statins Inhibit the biosynthesis of CoQ10.Acetaminophen depletes antioxidant defences.Tetracyclines

64. Drugs inducing mitochondrial damage (3)Many psychotropic medications

65. Proposed Aging Processes

66. Free Radicals and the Mitochondrial theory of AgingApoptosis is a mechanistic tool which enables organisms to get rid of redundant cells or cells being damaged beyond repair. Cytochrome C plays a key role in initiating the formation of the apoptosome which, in turn, activates the caspase pathway. Damage to the mitochondria would be likely to adversely affect the efficiency of their most important function, the synthesis of ATP. A significant slowing in the rate of ATP synthesis could readily lead to the types of declines in physiological functions that occur in aging.

67. Mitochondria and aging

68. The Theory of Aging and Mitochondria

69. Free Radicals and the Mitochondrial theory of AgingApoptosis is a mechanistic tool which enables organisms to get rid of redundant cells or cells being damaged beyond repair. Cytochrome C plays a key role in initiating the formation of the apoptosome which, in turn, activates the caspase pathway. Damage to the mitochondria would be likely to adversely affect the efficiency with which it performs its most important function, the synthesis of ATP. A significant slowing in the rate of ATP synthesis could readily lead to the types of declines in physiological functions that occur in aging.

70. Thank youFawwaz