BCH3021 Lecture Notes - Lecture 10: Superoxide Dismutase, Mitochondrial Disease, Leigh Disease
Lecture 10 – Mitochondrial Disease
Basis for Mitochondrial Disease
• Disorders are most frequent inborn errors of metabolism
• Refers to disease caused by disturbances of mitochondrial OXPHOS system ~
100 genetic disorders (LHON)
• Wide variety of clinical features in various combinations
(isolated/multisystemic)
o Muscle degeneration
o Cardiovascular disease
o Movement disorder
o Diabetes mellitus
o Renal failure
o Dementia
o Ophthalmological disorders
• Tissues with high energy demands generally affected (neural, muscle, brain_
o Any organ, any symptom, any age
• No cure
• Requirement for ATP
o Total cellular pool of ATP turned over every 1-2 minutes
Leigh Syndrome
• Most frequent mitochondrial disease
• Onset at ~2 years of age → progresses to brain disease (sub cortical
encephalopathy)
• Early onset of optic atrophy, opthalmoparesis, hypotonia, ataxia and dystonia
with death after several years
• Fluctuates in severity. Inter-current illness
• Genetically heterogenous: both nuclear and mtDNA mutations affecting many
different aspects of OxPhos but typically complexes I and IV
Abnormal Muscle Biopsies – Tissue Mosaicism
• Ragged red fibres (mitochondrial) revealed by tissue staining
o Reddish blotch in sub-sarcolemmal or inter-myofibrillar spaced
• SDH activity is high in cell complex while cytochrome oxidase activity is low
Mutations in both mtDNA and nuclear DNA can cause human Disease
• mtDNA highly susceptible to damage
o No protective histones
o Limited repair mechanisms
o Close proximity to ROS produced by electron transport chain
Oxidative Stress (ROS: reactive oxygen species)
• Produced by complexes themselves
• Mitochondria major source of ROS in cell
• Include
o Superoxide anion O22- produced by one electron reduction of O2
▪ Complex I is major producer of superoxide anion
▪ Converted to H2O2 by superoxide dismutase (SOD)
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Document Summary
Basis for mitochondrial disease: disorders are most frequent inborn errors of metabolism, refers to disease caused by disturbances of mitochondrial oxphos system ~ Leigh syndrome: most frequent mitochondrial disease, onset at ~2 years of age progresses to brain disease (sub cortical encephalopathy, early onset of optic atrophy, opthalmoparesis, hypotonia, ataxia and dystonia with death after several years, fluctuates in severity. Inter-current illness: genetically heterogenous: both nuclear and mtdna mutations affecting many different aspects of oxphos but typically complexes i and iv. Abnormal muscle biopsies tissue mosaicism: ragged red fibres (mitochondrial) revealed by tissue staining, reddish blotch in sub-sarcolemmal or inter-myofibrillar spaced, sdh activity is high in cell complex while cytochrome oxidase activity is low. Mutations in both mtdna and nuclear dna can cause human disease: mtdna highly susceptible to damage, no protective histones, limited repair mechanisms, close proximity to ros produced by electron transport chain.
