Mitochondrial Disorders - Unit 8 PDF

Unit 8 Mitochondrial Disorders everything memo Bowen Li, Ph.D. Oct-23-2024 * Dynamics of Mitochondrial Adaptation and Maintenance biogenesis : synthesis of new met* - creation ofnew mitochondria one + to...

Unit 8 Mitochondrial Disorders everything memo Bowen Li, Ph.D. Oct-23-2024 * Dynamics of Mitochondrial Adaptation and Maintenance biogenesis : synthesis of new met* - creation ofnew mitochondria one + to 2. fission : dividing into 2 m+ fusion : 2 me fuse intol 2 to generate Atp ↳ climinate repair : fix minor damage preventing degradation ↑ distinctional mitophagy selective form of apoptosis parts : Mitochondria undergo dynamic processes such as biogenesis, fission, fusion, repair, and mitophagy to adapt, ensure A dama tix Minor data on functionality, and maintain cellular health. selective form of apoptopy. I useverly damaged it 2 https://doi.org/10.1016/j.mad.2020.111212 * Mitochondria produces reactive oxygen species (ROS) more toxic Q : Which complex does not pump proton ? to cells Y It 8 ROS is a natural by-product of electron transport chain activity (including free radicals and non-radical reactive oxygen molecules, while free radicals specifically refer to molecules with unpaired electrons) Increased production of ROS can damage proteins, lipids, and DNA, and promote DNA mutations and genetic instability. Mitochondrial oxidative damage leads to the release of cytochrome c into the cytosol resulting in cell apoptosis. a programmed death 3 Mitochondrial Genome Maintenance: Damage and Repair Pathways selectively remove overtime , damaged MADNA : to preserve healthy replicates mutant maintain MtDNA & homeostasis Repair healthy fuses wasosome canother a · mechani - surpassed X Mitophagy release factors into cytosol to get apoptosis cytochromecrelease DOI: 10.5772/intechopen.84627 4 * Mitochondrial Disorders Mostly resulted from mutations in mitochondrial DNA (mtDNA) due to replication errors, external factors, and oxidative stress. These genetic mutations can lead to a failure in the assembly of the respiratory chain enzyme complexes and ATP synthase, which impinge upon mitochondrial oxidative phosphorylation. They can also result from mutations in nuclear DNA affecting mitochondrial functions. mtDNA Allmtdisorders are due to mutations in & 4 FALSE ! 5  The Complexity & Variability of Mitochondrial Disorders Mitochondrial disorders result in diverse clinical signs. Some inherited deficiencies don't hinder fetal growth but can lead to post-birth diseases: organ failure, and lactic acidosis. Some recover after the critical phase while others face later-life disorders. for in need Age & Organ Sensitivity: oxidative ↓ phosphorylative Post-birth oxidative phosphorylation needs surges. Organ vulnerability varies with age. Grain heart , , muscle more vulnerable b/c need for O2. energy. 6 * The Complexity & Variability of Mitochondrial Disorders The level of mutant mitochondrial DNA can vary from one organ to another within a single individual, and it is only when a significant part of the mitochondria of a particular tissue contains defective genetic information that clinical symptoms usually appear. over time mutant mtDNA mutant mtDNA surpasses WJ mtDNA ↓ patient displays symptoms heteroplasmy : both mutant + WT MIDNA are present in same cell Because of this variability, members of a family carrying the same mitochondrial DNA mutation can exhibit strikingly different symptoms and severity of the condition. I reason why disorders are unpredictable and hard to manage, 7  Outcomes of mitochondrial diseases In most cases, mitochondrial diseases are characterized by degeneration of muscle or brain, both of which utilize exceptionally large amounts of ATP. These conditions range in severity from diseases that lead to death during infancy, to diseases that produce blindness, deafness, or stroke, to milder conditions characterized by intolerance to exercise or production of nonmotile sperms (male infertility). 8  Primary vs. Secondary Mitochondrial Disorders Primary Mitochondrial Disease (PMD): Directly caused by genetic mutations that affect mitochondrial function. These mutations can be in the mitochondrial DNA (mtDNA) or in the nuclear DNA that encodes for mitochondrial components. don't can still be from father bir though Origin: Often inherited from one or both parents. > - can receive nuclear get ot from father PNA , Scope: Specifically targets the mitochondria, leading to a range of mitochondrial diseases, often from birth or early in life. Examples: MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) and LHON (Leber's Hereditary Optic Neuropathy). 9  Primary vs. Secondary Mitochondrial Disorders Secondary Mitochondrial Dysfunction: Not directly due to genetic mutations in mitochondrial genes but arises as a secondary consequence of other diseases or conditions. Origin: Could be caused by drugs, toxins, other genetic diseases affecting non- mitochondrial genes, or environmental factors. Scope: Typically part of broader cellular or systemic dysfunctions; mitochondria dysfunction is a component but not the sole issue. Examples: Some neurodegenerative diseases like Parkinson's and Alzheimer’s might have secondary mitochondrial dysfunctions as part of their pathology. 10  muscle MELAS v of buildup nervoustatem lactic acid ↓ ↓ (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) primary it disorder 11 ↓ ATP in astrocytes in CNS Cregulate neural activity) test affects Nat1k+ pump , uptake of glutamine into , & not on (for understanding & astrocute talutamine in synaptic crelt - excitotoxicity. which leads to neuronal death MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) MELAS is mostly caused by mutations in the genes in mtDNA or nucelar DNA. It primarily impacts the brain, nervous system (encephalo-), and muscles (myopathy). Typically begins in childhood; diagnosis common between ages 2 and 15. Extremely rare ( 1 in 4,000 people); ~75% of cases diagnosed before age 20. Most individuals with MELAS experience lactic acidosis (buildup of lactic acid in the body). Increased acidity in the blood can lead to various symptoms: scommon way to diagnose Vomiting lots of ht damag Abdominal pain accumsisting Extreme tiredness (fatigue) in periphery. Muscle weakness Loss of bowel control Difficulty breathing Muscle biopsy of a MELAS patient Seizure (which are like big, scary shakes) 12 * disorders the mt none of ↓ have curative treatment MELAS Therapies There is no curative treatment. The disease remains progressive and fatal. Mostly, it is symptomatic treatment. Nutrients 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. himmunoacid that transforms fats to energy In patients with mitochondrial myopathies in general, moderate treadmill training may result in an improvement of aerobic capacity and a drop in resting lactate levels. Anti-convulsant drugs (e.g. lamotrigine) to help prevent and control seizures associated with MELAS (Valproic acid should not be used as an anticonvulsant due to its potential to worsen mitochondrial dysfunction and lactic acidosis). 13 Leber hereditary optic neuropathy (LHON) primarymt disorder 14  t aiwy unsetsouwarene snow symptoms until reaches significant level. transmits info from Leber hereditary optic neuropathy (LHON) ↳ Y eletobrain not testedmechanism : mutation - impaired on ETC + ATP production , affect retinal ganglion cells, optic nerve degeneration LHON is a maternally inherited genetic disorder that causes sudden vision loss due to optic nerve damage. may preserve peripheral vision damage central vision > - + to LHON occurs at the rate of approximately 1:50,000 people and often appears in young adulthood, typically between the ages of 15 and 35. However, onset can occur at any age, including childhood or later in life. 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. 15 * Pedigree of LHON " maternally inherited All the progeny of an affected male (shaded in squares) are normal, but all children, male and female, of the affected female (shaded circles) manifest disease. 16 * LHON: standard management Although there is no cure, treatment aims to support affected individuals and potentially slow the progression of the disease. Supportive management: prescription eyewear, low-vision aids, and vision rehabilitation programs. Affected individuals should avoid smoking and excessive alcohol consumption, which generate reactive oxygen species (ROS) producing/ aggravating mitochondrial impairments. Idebenone Therapy: investigational medication to enhance cellular energy production, potentially benefiting the optic nerve cells. synthetic analogue of - > coenzyme Q10 CoQ Genetic counseling: helps individuals and families understand the genetic basis of the condition and make informed decisions. 17  when mother observes it disorders- want to have children (avoid passing defective Mitochondrial replacement therapy of PMD mrDNA) 3 people IVF This is a modified form of in vitro fertilization that allows women with mitochondrial disorders to avoid passing their defective mitochondria to their children. The method involves Q: Why doesn't paternal not get passed ? transferring the nucleus from the mother into an enucleated I is degraded egg from a donor with healthy mitochondria. https://sitn.hms.harvard.edu/flash/2018/mitochondrial-transfer-making-three-parent-babies/ 18 Alzheimer’s disease secondary it disorder 19  Alzheimer’s disease (AD) Alzheimer’s disease is the most common form of adult-onset dementia. An 80-year-old person has about a 30% chance of developing Alzheimer’s disease. Bamyloid target of drugs Hallmarks of Alzheimer’s: 1. Amyloid Plaques: These are abnormal protein deposits primarily made up of beta-amyloid protein. Found between brain nerve cells, they disrupt neuronal function, potentially contributing to disease progression. 2. Neurofibrillary Tangles (NFTs): NFTs are abnormal accumulations of tau protein within nerve cells. In Alzheimer's, phosphorylated tau aggregates into NFTs, impairing neuronal transport and function. 20 https://doi.org/10.1038/s41380-022-01631-6  AD and mitochondria Factors Leading to Mitochondrial Dysfunction: Aging, genetics, lifestyle, and environment affect mitochondrial health. Mitochondrial Dysfunction and Its Consequences: Abnormal Cellular Metabolism Oxidative Stress through releas > - mtDNA Damage of oxidative free radicals Decreased Respiration From Mitochondrial Dysfunction to AD: Accumulation of amyloid-beta (Aβ) peptides. Neuroinflammation. release signals triggering > - immun responses Neurodegeneration. i cognitive decline 21 DOI:10.1002/ana.25410  AD management B-amyloid. 22 * => know mechanism , drugs AD medications 1. AChE (acetyl cholinesterase) inhibitors: They offer symptomatic relief by inhibiting acetylcholine (ACh) turnover and restoring synaptic levels. 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 Exelon® (rivastigmine), and Aricept® (donepezil). numm num 2. NMDA (N-methyl D-aspartate) antagonist: blocks the NMDA receptor for glutamate, a neurotransmitter. 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. Examples include Namenda® (memantine) ummus 23 Parkinson’s Disease (PD) secondarymt disorder 24  Parkinson’s 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’s disease affects about: 0.4% of people > 40 yr 1% of people ≥ 65 yr 10% of people ≥ 80 yr The mean age at onset is the age of 60 years. It is usually idiopathic. ↳ cause is unknown neurons involves gradual loss of dopamine producing https://stanfordmedicine25.stanford.edu/the25/parkinsondisease.html 25  Pathology of PD Loss of the “substantia nigra” (dopamine) - ↳ critical brain region for the production of dopamine Normal substantia nigra. Depigmented substantia nigra in idiopathic Parkinson’s disease. diminished substantic nigra 26 * Striatum Parkinson’s disease: pathology striatum is a deep region of the forebrain involved in action selection , control of movement + motivation , ↳ need dopamine for these functions There is a reduction in the striatal dopamine content. The severity of the motor syndrome is proportional to the dopamine deficiency, which can be partially substantia postsynaptic nigra neurons corrected by replacement therapy with neuron L-DOPA (Levodopa), the immediate precursor of dopamine. In book: Early Detection of Neurological Disorders Using Machine Learning Systems (pp.61-95) Publisher: IGI Global 27  Parkinson's disease and mitochondria Factors Leading to PD-related Mitochondrial Dysfunction Genetic Mutations Neurotoxins and Environmental Toxins Oxidative Stress generation of ROS > - Mitochondrial DNA (mtDNA) Mutations Mitochondrial Dysfunction and Its Consequences Energy Deficits ↓ ATP production Increased Oxidative Stress damaging cellular regulation Impaired Calcium Regulation and Ageing Altered Protein Homeostasis From Mitochondrial Dysfunction to PD Neuronal Damage Alpha-Synuclein Aggregation (i.e., Lewy bodies) * Inflammation and Immune Response 28  PD management While there is no cure for PD, several strategies aim to alleviate symptoms, enhance quality of life, and slow disease progression. 29 * PD medications Why cannot we use dopamine in the treatment of PD? 1 o dopamine unable to Cross BBB · causes peripheral nervous system side effect. 30  Drug-induced mitochondrial damage With the increasing use of pharmaceutical medications, there has been a rise in health conditions linked to mitochondrial dysfunction and this dysfunction has been increasingly implicated in the etiology of drug-induced toxicities. Damage to mitochondria might explain the side effects of many medications. In severe cases, impairment of energy production could contribute to liver failure, coma, and even death. 31 * Examples of Drugs inducing mitochondrial damage Barbiturates were the first medication noted to impede mitochondrial function by inhibiting complex I. The same mechanism also explains how rotenone, an agricultural pesticide, causes mitochondrial damage. Rotenone happens to be useful in inducing animals to become study models for Parkinson’s disease. Statins (cholesterol-lowering drugs) may inhibit the biosynthesis of CoQ10. Anti-retroviral drugs used for treating HIV infections can inhibit the enzyme, mitochondrial DNA polymerase responsible for mitochondrial DNA replication. ↳ affects mechanism of repair 32 * Mitochondrial Theory of Aging Transition mutations or/and transversion mutations in mitochondrial DNA (mtDNA) would likely compromise 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. transition mutations more frequently - leads to transition mutation 2 types of DNA mutations cotransitions (2) transversions Y purine to pyrimidin or vice versa - 33 # Mitochondria and longevity oxidative stress -reduced Larger animals typically have slower metabolic rates, often leading to longer lifespans. Birds, however, defy this rule, boasting both fast metabolic rates and extended lifespans with reduced susceptibility to Tortoises age-related diseases. This exception can be attributed, at least in part, to the exceptional efficiency of bird mitochondria, resulting in fewer harmful free radicals. Laysan albatross Avian physiology's unique aspect of efficient mitochondria holds potential implications for understanding aging processes, reducing the risk of degenerative diseases, and impacting overall longevity. 34