p53 is required for nuclear but not mitochondrial DNA damage-induced degeneration

Abstract

While the consequences of nuclear DNA damage have been well studied, the exact consequences of acute and selective mitochondrial DNA (mtDNA) damage are less understood. DNA damaging chemotherapeutic drugs are known to activate p53-dependent apoptosis in response to sustained nuclear DNA damage. While it is recognized that whole-cell exposure to these drugs also damages mtDNA, the specific contribution of mtDNA damage to cellular degeneration is less clear. To examine this, we induced selective mtDNA damage in neuronal axons using microfluidic chambers that allow for the spatial and fluidic isolation of neuronal cell bodies (containing nucleus and mitochondria) from the axons (containing mitochondria). Exposure of the DNA damaging drug cisplatin selectively to only the axons induced mtDNA damage in axonal mitochondria, without nuclear damage. We found that this resulted in the selective degeneration of only the targeted axons that were exposed to DNA damage, where ROS was induced but mitochondria were not permeabilized. mtDNA damage-induced axon degeneration was not mediated by any of the three known axon degeneration pathways: apoptosis, axon pruning, and Wallerian degeneration, as Bax-deficiency, or Casp3-deficiency, or Sarm1-deficiency failed to protect the degenerating axons. Strikingly, p53, which is essential for degeneration after nuclear DNA damage, was also not required for degeneration induced with mtDNA damage. This was most evident when the p53-deficient neurons were globally exposed to cisplatin. While the cell bodies of p53-deficient neurons were protected from degeneration in this context, the axons farthest from the cell bodies still underwent degeneration. These results highlight how whole cell exposure to DNA damage activates two pathways of degeneration; a faster, p53-dependent apoptotic degeneration that is triggered in the cell bodies with nuclear DNA damage, and a slower, p53-independent degeneration that is induced with mtDNA damage.

Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-κB and p53 Pathways in Neurodegeneration

“…Recently, it has been shown that exposure of a whole cell to DNA damage activates p53-dependent apoptotic degeneration in the cell bodies, but p53-independent axonal degeneration after selective mtDNA damage [161]. In fact, some transcriptional targets of p53 are involved in the maintenance of mtDNA.…”

Establishment of a nonradioactive DNA ligation assay and its applications in murine tissues

“…This might be based on the particular anatomical structure of the cerebellum, as there are for example, strong differences between gray and white matter in addition to the characteristic layering. Both affect the distribution of cell soma where most metabolic processes as well as DNA repair take place (Geden et al, 2021). Consequently, cerebellum tissue might need to be homogenized for robust assessment of DNA ligation efficiency.…”

Genes and Longevity of Lifespan

“…Activated p53 is recognized as the master regulator of cell cycle, aging, apoptosis. P53 is required for cellular degeneration by genomic DNA damage not required for mitochondrial DNA damage response [323]. In fact a balance of antioxidant and prooxidant activities by p53 in response to oxidative stress play an important role in the longevity of lifespan [324] (Figure 3).…”