MRC Chain and Biogenesis Defects Flashcards
Define Heteroplasmy
Because each cell contains thousands of mitochondria, each containing 2-10 copies of DNA, nearly all organisms house low levels of mitochondrial variants, conferring some degree of heteroplasmy. Although a single mutational event might be rare in its generation, repeated mitotic segregation and clonal expansion can enable it to dominate the mitochondrial DNA pool over time. When this occurs, it is known as reaching threshold, and it usually results in physiological consequences
How is heteroplasmy invoked
This is through 2 levels:
- Cellular Division in which mitochondria pertaining different variants are spread unto different cells
- Fission and Fusion - Meaning mtDNA variants are mixed between mitochondria
What can protein coding and rRNA mutations lead to…
Haplo-insufficiency, in which the phenotypic expression will relate to the proportion of mutant mtDNA and its distribution amongst cell populations
What is the Threshold for deletion?
50%
What is the threshold for tRNAle mutation (A3243G)
90%
- this encodes the transcription stop site
Why do deletions require a lower mutant load?
This is because a Deletion typically results in the loss of functional protein, or the lowering of efficient transcription which can have huge direct effects on MRC components and other aspects of mitochondrial function
Whilst tRNA deletion simply results in a lowered translational efficiency
Why can 10% of Wt functional mtDNA for leutRNA give functional mito?
This is thanks to the role of complementation - in which a mitochondrial will hold several copies of mtDNA (2-10) within itself, these might present functional mtDNA wil 90% normal
How does complementation complement the theory of ageing?
The theory of ageing suggests that overtime mitochondrial defects will accumulate in teh cell, overtime, we can continue surviving pass this accumulation thanks to complementation - however, once we have suprassed a threshold there is no going back
Who proved the theory of complementation?
Hayashi et al. 1991
What are the two components of the threshold effect?
How much mutant mtDNA is required to give an MRC defect.
What level of MRC defect gives rise to cell dsyfunction.
How can mutations generate more mutations?
- Increase in ROS due to MRC defects
- Altered local cellular environments which can lead to amplifications in specific mutations
- MRC changes that adversly interact with cell specific mitocondrial regulation
What do primary mutations refer to?
Defects to the MRC
Describe a disease owed to Complex I mutations
–> which is NADH dehydrogenase
Leigh’s Disease (AR)
–> This leads to decreased MRC activity and compromised ADP phosphorylation - why this primarily effects the CNS is unclear
Describe a disease owed to Complex II mutations
–> Succinate dehydrogenase
2 Families with Leigh’s disease
Describe inhibitors of Complex I
Rotenone and 1-methyl-4-phenyl-1,2,3,6 -tetrapryrimidine –> Parkinosnism
Describe inhibitor of Complex II
3 nitroproprionic acid –> HD like disease
What do the symptoms induced by complex inhibitors imply?
That MRC defects could underlie the pathology of these diseases
What do I mean by Secondary mutations?
Indirect effectors of the MRC
- MRC assembly
- mtDNA regulation
- mitochondria quality control
What does SURF1 encode
Surfeit and it is required for insertion of COX II subunit insertion into complex IV
Give an example of a mutation effect MRC assembly
SURF1
Give an example of a mutation effecting mtDNA regulation
- TK2 (mitochondrial thymidine kinase gene)
- dGK (mitochondrial deoxyguanosine kinase)
- These lead to mtDNA depletion syndrome
What does TK2 stand for
Mitochondrial thymidine kinase
What does dGK stand for
dexyguanosine kinase
What do TK2 and dGK do?
These lead to mtDNA depletion syndrome, the genes encode proteins important in the salvage of nt required for mtDNA replication, so their deletion results in the imbalance of dNTP for mtDNA replication
What leads to mtDNA deletion (not depletion)
- DNA polymerase Gamma
- Twinkle
- Thymidine Phosphorylase Gene
What do mutations in POLG, Twinkle and Thymidine Phosphorylase lead to
Influence proteins involved in mtDNA replication, mutation in particular effects the fidelity of replication causing multiple deletions
What are mutations that could effect mitochondrial quality control?
Pink1 parkin
Fission and fussion genes
- Damaged mito are not degraded efficiently which leads to the accumulation of damaged/truncated mito
What species could damage MRC
Free radical and NOx
