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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