Mitochondrial DNA degradation: A quality control measure for mitochondrial genome maintenance and stress response

Abstract

Mitochondria play a central role in bioenergetics, and fulfill a plethora of functions in cell signaling, programmed cell death, and biosynthesis of key protein cofactors. Mitochondria harbor their own genomic DNA, which encodes protein subunits of the electron transport chain and a full set of transfer and ribosomal RNAs. Mitochondrial DNA (mtDNA) is essential for cellular and organismal functions, and defects in mitochondrial genome maintenance have been implicated in common human diseases and mitochondrial disorders. mtDNA repair and degradation are known pathways to cope with mtDNA damage; however, molecular factors involved in this process have remained unclear. Such knowledge is fundamental to the understanding of mitochondrial genomic maintenance and pathology, because mtDNA degradation may contribute to the etiology of mtDNA depletion syndromes and to the activation of the innate immune response by fragmented mtDNA. This article reviews the current literature regarding the importance of mitochondrial DNA degradation in mtDNA maintenance and stress response, and the recent progress in uncovering molecular factors involved in mtDNA degradation. These factors include key components of the mtDNA replication machinery, such as DNA polymerase γ, helicase Twinkle, and exonuclease MGME1, as well as a major DNA-packaging protein, mitochondrial transcription factor A (TFAM).

Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging

“…Class 3 deletions do not respect these potential origins of replication, and they are uniformly distributed throughout the genome in young Gwt samples without regard for deletion size or TMH length. Class 3 deletions are expected to form by mechanisms independent of DNA replication [ 33 , 75 , 76 ]. Mitophagy and other phenotypic selectors for mitochondrial survival are not needed to explain these patterns.…”

“…One mechanism becomes less frequent with age and has features expected for replication-independent deletions, such as ligation of random strand breaks or interruption of DNA repair events. Incomplete degradation of damaged mtDNA [ 76 ] also presents opportunities to form mtDNA deletions with random lengths and positions. The other two mechanisms are synergistic, become more frequent with age, and have features that imply replication dependence.…”

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

“…We hypothesized that the increase in mtDNA integrity in NEK5 cells could be related to mtDNA turnover and mitochondrial biogenesis, as NEK5 WT cells also showed a slight decrease in mtDNA copy number; thus, the increase in integrity would be a consequence of mtDNA turnover. TFAM is highly related to mtDNA content, degradation, and, consequently, turnover [48]; PGC-1a is a major regulator of mitochondrial biogenesis and activates different transcription factors, including nuclear respiratory factor 1 and nuclear respiratory factor 2, which also activates TFAM [49,50]. We evaluate the expression level of those genes and both, PGC1a and TFAM, do not vary significantly although PGC1a tend to be more expressed in NEK5 WT and NEK5 K33A cells (Fig.…”

The Aging Stress Response and Its Implication for AMD Pathogenesis

“…These and other studies suggest that AMD may be associated with an energetic crisis in the RPE [ 94 ]. However, other consequences of impaired mtQC in AMD were reported, including disrupted intracellular calcium homeostasis and nuclear-mitochondrial signaling [ 94 , 156 ].…”