The Maintenance of Mitochondrial DNA Integrity and Dynamics by Mitochondrial Membranes

Abstract

Mitochondria are complex organelles that harbour their own genome. Mitochondrial DNA (mtDNA) exists in the form of a circular double-stranded DNA molecule that must be replicated, segregated and distributed around the mitochondrial network. Human cells typically possess between a few hundred and several thousand copies of the mitochondrial genome, located within the mitochondrial matrix in close association with the cristae ultrastructure. The organisation of mtDNA around the mitochondrial network requires mitochondria to be dynamic and undergo both fission and fusion events in coordination with the modulation of cristae architecture. The dysregulation of these processes has profound effects upon mtDNA replication, manifesting as a loss of mtDNA integrity and copy number, and upon the subsequent distribution of mtDNA around the mitochondrial network. Mutations within genes involved in mitochondrial dynamics or cristae modulation cause a wide range of neurological disorders frequently associated with defects in mtDNA maintenance. This review aims to provide an understanding of the biological mechanisms that link mitochondrial dynamics and mtDNA integrity, as well as examine the interplay that occurs between mtDNA, mitochondrial dynamics and cristae structure.

NEK5 interacts with LonP1 and its kinase activity is essential for the regulation of mitochondrial functions and mtDNA maintenance

“…The human mtDNA is a double-stranded circular structure containing 37 genes, which encodes essential components of the oxidative phosphorylation system (OXPHOS), and components of the mitochondrial translation system, transfer, and ribosomal RNA molecules [23]. A typical mammalian cell harbors between 1000 and 10 000 copies of the mtDNA genome that exist in a DNA-protein complex, termed nucleoid.…”

“…The compaction of mtDNA is attributed to TFAM (transcription factor A, mitochondrial), that specifically binds along the mtDNA, instigating bending and looping, resulting in a nucleoid tightly compacted. The stable protein filaments that are formed between TFAM and mtDNA prevent POLRMT-mtDNA RNA polymerase-and TWINKLE-mtDNA helicase -from accessing the mitochondrial genome [23]. LonP1, an AAA+ mitochondrial protease, specifically degrades phosphorylated TFAM, leading to mtDNA unwind, influencing mtDNA transcription and nucleoid dynamic [24].…”

Role of Oxidative DNA Damage and Repair in Atrial Fibrillation and Ischemic Heart Disease

“…Mitochondria are also the only organelle, besides nuclei, containing their own DNA and machinery for synthesizing RNA and proteins [ 60 ]. All 13 mitochondrial DNA (mtDNA) encoded proteins are essential components of OXPHOS complexes I, III, IV, and V [ 61 ], and mutations in mtDNA can directly impact the essential function of ATP production and the concomitant ROS generation. MtDNA does not contain histones, and hence is thought to be more prone to oxidative damage [ 62 ].…”

“…Mitochondria also possess several pathways for the repair of mtDNA damage, in particular the base excision repair (BER) pathway [ 67 , 68 ], which is described in detail below. Deficient repair of damaged mtDNA can lead to a dramatic accumulation of mtDNA molecules harboring deletions and a significant reduction in mtDNA copy number [ 61 , 69 ], which was shown to be associated with a higher risk of cardiovascular diseases, including sudden cardiac death [ 70 ]. Furthermore, various studies show that continuous damage to mtDNA can eventually result in nuclear mutations of genes encoding mitochondrial proteins, further triggering mitochondrial dysfunction in various diseases, suggesting a crosstalk between mtDNA and nuclear DNA [ 71 , 72 , 73 , 74 ].…”

Advances in mt-tRNA Mutation-Caused Mitochondrial Disease Modeling: Patients’ Brain in a Dish

“…These illnesses can be caused by mutations in nDNA or mtDNA. These mutations affect not only genes encoding for MRC components but also those that are involved in protein translation and assembly, mtDNA stability, as well as mutations in those nDNA-encoded proteins involved in the maintenance of mitochondrial nucleotide pools, nucleotide transport, mtDNA replication, RNA transcription, and mitochondrial dynamics ( Schon et al, 2012 ; Chapman et al, 2020 ). Mitochondrial diseases are clinically heterogeneous; they may occur at any age, and patients manifest a wide variety of symptoms ( Gorman et al, 2016 ).…”