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![REDUCE ENERGY UPTAKE
SIR2 expression is activated by CRAN (Caloric
Restriction with Adequate Nutrition), but neither CRAN
nor extra SIR2 can silence genes without NAD+
(oxidized form of Nicotinamide Adenine Dinucleotide)
as a co-factor
(SCIENCE 289:2126-2128 (2000)])
The presence of a
high NAD/NADH ratio
in a cell is an index of
low energy
production.
26/11/55 58
KLENTZE MEDICAL INSTITUTE](https://image.slidesharecdn.com/20230416mitochondrialdysfunction-240612074639-51a2ed4e/75/Mitochondrial-dysfunction-in-medical-pptx-58-2048.jpg)
![RESVERATROL，白藜芦醇
Treatment of fibroblasts with the
SIRT1 activator resveratrol
resulted in a significant
reduction of fat
content [NATURE; Picard,F;
429:771-776 (2004)].
1
Polyphenols such as quercetin,
resveratrol (especially) and other
sirtuin-activating compounds
have been reported to extend
the lifespan of nematodes &
fruit flies.
2
Resveratrol was shown to extend
lifespan of nematodes by 10%
and fruit flies by 29% without
loss of fertility [NATURE;
Wood,JG; 430:686-689 (2004)]
3](https://image.slidesharecdn.com/20230416mitochondrialdysfunction-240612074639-51a2ed4e/75/Mitochondrial-dysfunction-in-medical-pptx-60-2048.jpg)
Mitochondrial dysfunction in medical.pptx
- 1.
- 2. MITOCHONDRIA STILL A MICROBE,BUT WITH LESS BAGGAGE • The mitochondria, an alpha- proteobacterium who joined forces with a larger cell two billion years ago to form our own eukaryote cells, has gradually shed DNA to the larger cell, in order to become an effective intracellular powerhouse • .
- 3. OXIDATIVE PHOPHORYLATION • Along themembrane inside the mitochondria, the elaborate respiratory complex and the Krebs cycle transfer electrons to oxygen forming an electrochemical gradient that transfers protons to make most of the cell’s high energy particles.
- 7. • Mitochondria oxidizemolecules capturing the bond energy, which is made available in the form of energy rich molecules ATP, GTP NADH2 and NADPH2. It also uses this gradient to buffer calcium signaling. • When this gradient fails, the mitochondria is defective and signals prepare for its repair or destruction.
- 9. Dynamic Control of Energy Needs and theNumber of Mitochondria • When mitochondria have spent their ability to maintain a gradient for transfer of electrons, they are either restored by the energy of other comrades through fusion, or they are moved to a process of destruction through division.
- 10. MITOCHONDRIAL DISEASES Mitochondrial diseases arechronic (long- term), genetic, often inherited disorders that occur when mitochondria fail to produce enough energy for the body to function properly. Mitochondrial diseases can affect almost any part of the body, including the cells of the brain, nerves, muscles, kidneys, heart, liver, eyes, ears or pancreas.
- 11. MITOCHONDRIAL HEREDITARY DISEASES ALZHEIMER MUSCULAR DYSTROPHY LOUGEHRING (ALS) LEBERS HEREDITARY OPTICUS NEUROATROPHY (LHON) DIABETES CANCER
- 12. • One in5,000 individuals has a genetic mitochondrial disease. Each year, about 1,000 to 4,000 children in the United States are born with a mitochondrial disease.
- 13. MITOCHONDRIAL INHERITANCE: In thisunique type of inheritance, the mitochondria contain their own DNA. Only mitochondrial disorders caused by mutations in the mitochondrial DNA are exclusively inherited from mothers. If this is the way a mitochondrial disease was inherited, there is a 100% chance that each child in the family will inherit a mitochondrial disease.
- 14. RANDOM MUTATIONS: Sometimes genes develop amutation of their own that is not inherited from a parent.
- 15. ROLE OF MITOCHONDRIAAS GENERATOR OF FREE RADICALS AND MITOCHONDRIAL AGING Mitochondria: red: Energy, white: free radicals GEO, 02/2006 KLENTZE INSTITUT München 26/11/55 15 KLENTZE MEDICAL INSTITUTE
- 17.
- 18. Major Apoptotic Pathwaysin Mammalian Cells Hengartner, M.O. 2000. Nature. 407:770. Green, D. and Kroemer, G. 1998. Trends Cell Biol. 8:267. Mitochondrial Pathway Death Receptor Pathway FasL Caspase 3 D D D D Fas/Apo1 /CD95 FADD Procaspase 8 DISC Caspase 8 BID oxidants ceramide others Bcl-2 D Cytochrome c dATP Procaspase 9 Apaf -1 dATP Apaf -1 Caspase 9 Procaspase 3 apoptosome DNA damage Cellular targets
- 19. Mitochondrial DNA mutation MitochondrialDNA is highly susceptible to damage produced by reactive oxygen species. Mt DNA is not protected by histones Little repair capacity Mutation of mt DNA lead to RC dysfunction, causing the release of even more ROS. Mt DNA mutations accumulate over time and become the most important cause of aging 26/11/55 Wiesner,R, Zsurka,G., Kunz,W :Free radical res. 2006;00(0),1-11 19
- 20. MITOCHONDRIAL DNA DAMAGE Mitochondrial DNAis highly susceptible to damage produced by reactive oxygen species. Mt DNA is not protected by histones Little repair capacity Mutation of mt DNA lead to RC dysfunction, causing the release of even more ROS. Mt DNA mutations accumulate over time and become the most important cause of aging Wiesner,R, Zsurka,G., Kunz,W :Free radical res. 2006;00(0),1-11 KLENTZE INSTITUT München
- 21. 26/11/55 21 KLENTZE MEDICALINSTITUTE
- 22. FREE RADICALS As thefree radical (green) attacks the membrane it can release another type free radical (blue).
- 23. Damaged membrane The free radical(blue) attacks the DNA releasing another free radical (purple). mitochondrion
- 24. anti-oxidant molecule repaired membrane damaged DNA The anti-oxidant moleculedestroys the damaging free radical. The membrane repairs itself, but the DNA remains damaged, impairing the cells function. In addition, the anti-oxidant molecule now has an unpaired electron and thus becomes a new radical.
- 25.
- 26. MAIN SYMPTOMS OF MITOCHNDRI AL DYSFUNCTIO N – FATIGUE ANDMUSCLE WEAKNESS Mitochondrial dysfunction is directly related to decreased production of ATP as well as being directly related to excessive and chronic fatigue. Fatigue is the most common complaint in a medical office and is an important secondary condition in many disease states. Oxidative damage to the mitochondrial membrane impairs mitochondrial function.
- 27. SYMPTOMS Poor growth. Muscle weakness,low muscle tone, exercise intolerance., muscle pain Vision and/or hearing problems. Learning disabilities, delays in development. Autism spectrum disorder Heart, liver , kidney diseases. swallowing difficulties,, cramping, reflux. Gastrointestinal, diarrhea , constipation unexplained vomiting
- 28. SYMPTOMS Diabetes. Increased risk ofinfection. Neurological problems, Seizures, migraine, strokes Movement disorders. Hypothyroidism Respiratory (breathing) problems. Lactic acidosis (a buildup of lactate). dementia 要特别注意甲状腺功能！
- 29. Diagnosis starts witha series of examinations and tests that may include: A review of a patient’s family history. A complete physical examination. A neurological examination. A metabolic examination that includes blood and urine tests, and, if needed, a cerebral spinal fluid test (spinal tap).
- 30. DIAGNOSTICS MRI Retinal exam or electroretinogram (ERG)for vision symptoms. ECG EEG Audiogram or auditory- brainstem evoked responses (ABER) for hearing symptoms. Blood test to detect thyroid dysfunction if the patient has thyroid problems. Blood test to perform genetic M- DNA testing.
- 31.
- 32. MITOCHNDRIA L DNA DUPLIKATION Inside ourcells, mitochondria multiply by dividing in half similar to bacteria. Unlike bacteria they can also fuse with other comrades in the cell. In addition, unlike other bacteria, they have many copies of circular DNA, made inside the mitochondria at times when the mitochondria is not dividing.
- 33. THERE ARE 100- 10,000DOUBLE STRANDED SEPARATE COPIES OF MITOCHONDRIAL DNA IN EACH CELL, EACH HAVING 15,000-17,000 BASE PAIRS. One circular strand is guanine-rich called the heavy strand with 28 genes, and the other cytosine-rich called the light strand with 9 genes. Of the 37 genes, 13 are for respiratory proteins , 22 are for transfer RNA and two are for the small and large subunits of the mitochondrial ribosome.
- 34. ALL OTHER PROTEINS USED INTHE MITOCHONDRIAL DIVISION AND FUSION ARE MADE IN THE NEURON’S NUCLEUS . Although only making 13 proteins themselves, mitochondria use more than 1,000 different proteins, which are different in different species and in different human tissues. Most proteins used by the mitochondria are transported and assembled by machines in the neuron’s endoplasmic reticulum. Many complex pathways regulate the building blocks of mitochondria, stimulated by nutrients, environment and other factors. The machinery is triggered and coordinated by protein factors and RNA signals. Mutations of any part of this process can lead to many different significant mitochondrial diseases, including cancer and Alzheimer, Parkinson’s and Huntington’s.
- 36.
- 37. Nucleoids are PackagedMitochondria DNA • The dance of producing more mitochondria and more energy is regulated through a complex system of quality control, from the communication of both ER and mitochondria, stimulating divisions and fusions. • Both the individual mitochondrion and the large mitochondrial network of the entire cell is regulated in this process directed from the ER.
- 39. Oxphos enzymes arecoded in mt DNA as well in nucleus DNA. There are many mutations known (inserts, deletions, single point mutations). They all cause disturbed energy production (There are some diseases known. Which present as a model for age related diseases: MERFF, MELAS, LHON After Wallace all this mutations are involved in • CVD • Diabetes Typ II • Parkinson • Alzheimer Double string DNA no repair mechanisms Mitochondrial DNA Mutation 26/11/55 39 KLENTZE MEDICAL INSTITUTE
- 40.
- 41. Blood test to detect MITOCHONDRIA Ldysfunction MITOCHONDRIAL FUNCTION (MEMBRANE POTENTIAL OF MITOCHONDROA) NITROTYROSINE，酪氨酸特别容易收到氮化损伤，RNS，vs ROS B VITAMIN PROFILE FATTY ACID OF THE RED CELL MEMBRANE，红细胞膜的脂肪酸 OX. STRESS : LIPIDOXIDATION, 9-OH DESOXYGUANIN，氧化压力 ANTIOXIDANT CAPACITY，抗氧化能力 THIOL STATUS (PROTECTIVE)，硫醇 SOD2，超氧化物歧化酶 COENZYME Q10 GSH/GSGG，越多GSH变成GSGG表示氧化压力越大
- 42. More advanced testing could include biochemical testing,which looks for changes in body chemicals that are involved in energy making. Skin and muscle tissue BIOPSY may also be performed.
- 43. NRF 2 The transcriptionfactor Nrf2 (NF-E2 p45-related factor 2) has emerged in the last few years as an important modulator of multiple aspects of mitochondrial function. Well-known for controlling cellular redox homeostasis, the cytoprotective effects of Nrf2 extend beyond its ability to regulate a diverse network of antioxidant and detoxification enzymes. Given the importance of mitochondria in the development of multiple diseases, these findings reinforce the pharmacological activation of Nrf2 as an attractive strategy to counteract mitochondrial dysfunction.
- 44. RHODANASE 可以产生thiol, 硫醇 •Mitochondria damage is related to a broad spectrum of pathologies including Alzheimer's, Parkinson's disease, and carcinogenesis. Recently, it has been found that reactive sulfur species (RSS) has a close connection with mitochondrial health. Rhodanese Rdl2 produces reactive sulfur species to protect mitochondria from reactive oxygen species ROS (Rhodanase) > RSS, which is less dangerous.
- 45. PGC ALPHA The transcriptionalco-activator peroxisome proliferator- activated receptor gamma coactivator 1 alpha (PGC-1α) has been characterized as a major factor in the transcriptional control of several mitochondrial components. PGC-1α is often described as a master regulator of mitochondrial biogenesis as well as a central player in regulating the antioxidant defense. PGC-1α is also involved in the complex regulation of mitochondrial quality beyond biogenesis, which includes mitochondrial network dynamics and autophagic removal of damaged mitochondria.
- 46. • Mitochondrial encephalomyopathy, lacticacidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequently inherited mitochondrial disorders. • MELAS syndrome is a systemic disease with multiple organ involvement. • The most common mutation in MELAS is the m.3243A>G mutation in the MT- TL1 gene.
- 47.
- 48. Interventions 26/11/55 48 KLENTZE MEDICALINSTITUTE 初榨橄榄油+辅酶Q10
- 49. VITAMINS AND SUPPLEMENTS •Coenzyme Q10; • B complex vitamins, especially thiamine (B1) and riboflavin (B2), B5, B7 • Alpha lipoic acid 精氨酸; • L-carnitine (Carnitor) 左旋肉碱; • Creatine 肌氨酸; • and L-Arginine 左旋精氨酸; • 褪黑素，绿茶，白藜芦醇.
- 50. • COENZYME Q10FUNCTION IN MITOCHONDRIA
- 51. COENZYME Q10 FUNCTIONIN MITOCHONDRIA 泛醌 泛醇（比较好）
- 52. L- CARNITINE FUNCTIONIN MITOCHONDRIA
- 53. MITOCHONDRIAL FUNCTION ANDTOXICITY: ROLE OF THE B VITAMIN FAMILY ON MITOCHONDRIAL ENERGY METABOLISM Thiamin (B1) is essential for the oxidative decarboxylation of the multienzyme branched-chain ketoacid dehydrogenase complexes of the citric acid cycle. Riboflavin (B2) is required for the flavoenzymes of the respiratory chain, while NADH is synthesized from niacin (B3) and is required to supply protons for oxidative phosphorylation. Pantothenic acid (B5) is required for coenzyme A formation and is also essential for alpha- ketoglutarate and pyruvate dehydrogenase complexes as well as fatty acid oxidation. Biotin (B7) is the coenzyme of decarboxylases required for gluconeogenesis and fatty acid oxidation. doi: 10.1016/j.cbi.2006.04.014.
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- 56. TAKE CARE OF THEGUT 我们的线粒体和肠内菌群是保持沟通互动的
- 57. Energy is thekey • Okinawan centenarians consume 10%–20% fewer calories per day than typical Americans. • And in animal studies, calorie- restricted diets have consistently increased the life span. • The old Okinawans consume less fat, too. About 26% of their energy intake comes from fat, compared with 30% or more for Americans. • And more of that fat is beneficial— omega-3 fatty acids and the unsaturated fats found in vegetable oils. • They eat many fruits and vegetables. • The Okinawans have an average of seven servings a day. • They get regular physical activity for as long as they are able. 26/11/55 KLENTZE MEDICAL INSTITUTE 57
- 58. REDUCE ENERGY UPTAKE SIR2expression is activated by CRAN (Caloric Restriction with Adequate Nutrition), but neither CRAN nor extra SIR2 can silence genes without NAD+ (oxidized form of Nicotinamide Adenine Dinucleotide) as a co-factor (SCIENCE 289:2126-2128 (2000)]) The presence of a high NAD/NADH ratio in a cell is an index of low energy production. 26/11/55 58 KLENTZE MEDICAL INSTITUTE
- 59. • 1.Is Resveratrola hope? • 2.Metformin mimics Caloric restriction 26/11/55 KLENTZE MEDICAL INSTITUTE 59
- 60. RESVERATROL，白藜芦醇 Treatment of fibroblastswith the SIRT1 activator resveratrol resulted in a significant reduction of fat content [NATURE; Picard,F; 429:771-776 (2004)]. 1 Polyphenols such as quercetin, resveratrol (especially) and other sirtuin-activating compounds have been reported to extend the lifespan of nematodes & fruit flies. 2 Resveratrol was shown to extend lifespan of nematodes by 10% and fruit flies by 29% without loss of fertility [NATURE; Wood,JG; 430:686-689 (2004)] 3
- 61. METFORMIN • Metformin resultsin the same gene expression seen in CRAN. • Metformin activates AMP-activated protein kinase (AMPK=AGE-1), an enzyme activated by low energy availability (adverse environment, food stress). • Activation of AMPK is required for metformin's inhibitory effect on glucose production by hepatocytes. • Activation of AMPK provides a unified explanation for the beneficial effects of metformin: activating AMPK increases life span in C. elegans, and metformin has been shown to increase life span in rodents 26/11/55 KLENTZE MEDICAL INSTITUTE 61