Defects in mitochondrial dynamics and mitochondrial DNA instability

Yu-Wai-Man, P; Lenaers, G; Chinnery, PF

doi:10.1007/978-1-4614-3722-2_9

Defects in mitochondrial dynamics and mitochondrial DNA instability

Lookup NU author(s): Dr Patrick Yu Wai Man, Professor Patrick Chinnery

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Abstract

© 2013 Springer Science+Business Media, LLC. All rights reserved. Mitochondria form a highly interconnected, dynamic, tubular network throughout the cell, with mitochondrial segments budding and fusing continuously in a process partly dictated by local physiological needs. Over the past two decades, key proteins have been identified that regulate the delicate balance between mitochondrial fusion and fission. The main pro-fusion proteins are OPA1, MFN1, and MFN2; and the main pro-fission proteins are DRP1, hFIS1, OPA3, and GDAP1. An important structural similarity shared by a number of these mitochondrial membrane-associated proteins is a highly conserved dynamin-related GTPase domain that is essential for their normal function. Clinically, a number of neurodegenerative phenotypes have been linked to mutations in these nuclear genes. Interestingly, mitochondrial fusion-fission imbalances in OPA1 and MFN2 disorders have also been associated with the accumulation of high levels of somatic mitochondrial DNA (mtDNA) deletions. This recently uncovered link between mitochondrial network disruption and mtDNA instability is mechanistically intriguing, clearly pointing towards shared disease mechanisms in the pathophysiology of these primary mitochondrial dynamic disorders.