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Dr. Aga Syed SameerCSIR Lecturer
Department of Biochemistry,
Medical College,
Sher-I-Kashmir Institute of Medical Sciences,
Bemina, Srinagar, Kashmir, 190018. India.
Biological
Oxidation
Mitochondrial Theory of Ageing &Diseases
Mitochondrial Damage & AgingOXPHOS generates chemical species with an
unpaired electron - called as Free Radicals
The most common “Reactive Oxygen Species (ROS’s)” are capable of independent existence & are highly reactive
ROS’s are produced at cytochrome oxidase by partial reduction in one-electron steps: by addition of one, two or four electrons to O2
Superoxide radical (O2-),
Hydrogen peroxide (H2O2).Hydroperoxyl (HO2), Hydroxyl radical (OH.)
Mitochondrial Damage & Aging
These ROS’s have the capability to cause damage to the cellular constituents which include:
Lipid Membrane, causing Peroxidation
Proteins, causing Enzyme inactivation
Mitochondrion itself, Shutting OXPHOS
mtDNA, by inserting mutations
Mitochondrial Damage & Aging
Free radical theory of aging - conceived by Denham Harman in the 1950s: now called as Mitochondrial theory of agingIt proposes that ROS’s that are produced in
the mitochondria, causes damage to lipids, proteins and most importantly mitochondrial DNA.
This damage then causes mutations which leads to an increase of ROS production and greatly enhances the accumulation of free radicals within cells.
Mitochondrial Damage & AgingThe superoxide anion directly affect the
intracellular enzymes such as epinephrine, creatine phosphokinase, lactate dehydrogenasebound NADH, aconitase, 6-phosphogluconate dehydrogenase
It is also capable of initiating the lipid peroxidation and causes the oxidation of thiols,
Also induces the sister chromatid exchange, chromosome breakage and has been implicated in O2 carcinogenesis.
Mitochondrial Damage & Ageing
Interactions of OH· with the DNA leads to the formation of many types of oxidized nucleosides, 8-hydroxy deoxyguanine is one of the most commonly occurring product of these DNA modifications
Formation of 8-OHdG is thought to be promutagenic lesion since this induces G:C to A:T transversion unless repaired prior to replication
Mitochondrial Genome
mtDNA is compact, double stranded, circular in nature
16569 bps in length
Consists of 37 genes, including 13 polypeptides, 22 tRNA and two rRNA genes
Mitochondrial DiseasesOut of 100 proteins that take part in ETC and
OXPHOS, 13 are coded by mtDNA
mtDNA is always maternally inherited
Also, mtDNA is 10x more vulnerable to mutations than nuclear DNA
Because of the mutations in the mtDNA many different diseases have been indentified in humans
MELASMitochondrial Encephalopathy Lactic Acidosis &
Stroke
Characterized by repeated episodes of chemical strokes, myopathy, intermittent vomiting, proximal limb weakness and lactic acidosis
Typical onset between the ages of 2 and 15
Occurs due to mutations in mt tRNAleu gene and also due to point mutations: A3243G in mtDNA
LHONLeber’s Heriditary Optic Neuropathy
Characterized by Acute/Subacute bilateral central vision loss; due to retinal degeneration
Onset usually occurs in patients in 20s/30s
Male:Female ratio: 4:1
Many mutations have been found in mtDNA; 3 most common ones account for 90% of the diseased condition
CPEOChronic Progressive External Opthalmoplegia
Kearns-Sayre Syndrome
Characterized by Opthalmoplegia, ptosis, atypical retinitis pigmentosa, ragged-red fiber myopathy, ataxia, deafness and cardiomyopathy
Onset usually occurs before the age of 20years
Most mutations involved are contiguous deletions/ duplication of the part of mtDNAcoding for tRNAs
MERRFMyoclonic Epilepsy with Ragged Red Fibers
Progressive disorder characterized by uncontrolled muscle contractions (myoclonicseizures), dementia, ataxia, myopathy which shows ragged-red fibers with specialised stains when biopsied
Mutation are in tRNAlys gene
NARPNeurogenic Muscle Atrophy & Retinitis
Pigmentosa & Leigh Disease
Characterized by pigmentary retinopathy in the presence of neuromuscular degeneration and subcutaneous necrotizing encephalopathy – with ataxia and basal ganglia degenration
Genetically heterogenous syndrome
Mutation are in ATP6 gene in mtDNA
Questions?
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