Directional Shift in Mitochondrial Heteroplasmy

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" Directional Shift in Mitochondrial Heteroplasmy "
Mohammad Naeem, Mansur Sondheimer, Neal

Document Type	:	Latin Dissertation
Language of Document	:	English
Record Number	:	1055360
Doc. No	:	TL54477
Main Entry	:	Mohammad Naeem, Mansur
Title & Author	:	Directional Shift in Mitochondrial Heteroplasmy\ Mohammad Naeem, MansurSondheimer, Neal
College	:	University of Toronto (Canada)
Date	:	2020
Degree	:	Ph.D.
student score	:	2020
Note	:	188 p.
Abstract	:	Diseases due to mitochondrial DNA (mtDNA) mutations are lethal and few therapeutic options are available. Because these mutations often exist in a state of heteroplasmy, the coexistence of wild-type and mutated mtDNA, strategies that can alter this ratio in favor of wild-type mtDNA (“heteroplasmy shifting”) may be therapeutically useful. We found that the Leigh syndrome (LS)-associated m.10191C variant promotes G-Quadruplex (GQ) formation within local sequence in vitro. The GQ formed at m.10191C differentially impeded the processivity of the mitochondrial DNA polymerase gamma (POLG) in vitro, providing a potential means to favor replication of the wild-type allele. Treatment of patient fibroblasts with GQBA induced alternating mtDNA depletion and repopulation and was effective in shifting heteroplasmy towards the non-pathogenic allele. Following treatment, heteroplasmic m.10191T>C cells had increased in maximal mitochondrial oxygen consumption. We developed a high-throughput assay to screen 23,000 GQBA for preferential binding to m.10191C allele with minimal off-target effects and two compounds were identified with favourable characteristics. We observed that mitochondria in patient cells harbouring pathogenic heteroplasmic mtDNA mutation are hyperfused compared to controls. Fragmenting mitochondria by knock down of fusion genes led to shift in mitochondrial heteroplasmy. This study demonstrates the potential for using small-molecule GQ-binding agents to induce genetic and functional shift in m.10191T>C mutation and mitochondrial fragmentation may have synergistic effects.
Descriptor	:	Genetics
	:	Molecular biology
	:	Neurosciences
Added Entry	:	Sondheimer, Neal
Added Entry	:	University of Toronto (Canada)