The role of mitochondrial DNA mutation on neurodegenerative diseases

Abstract

Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.

Figure 1

Schematic model of the communication between mitochondria and the nucleus. Signaling between mitochondria and the nucleus is tightly controlled under cellular homeostasis. However, excessive reactive oxygen species (ROS) production induces translocation of the p53 protein to the mitochondria and suppression of peroxisome proliferator-activated receptor-γ coactivator 1; inhibition of the mitochondrial electron transport chain (ETC) by oxidative stress results in alteration of the nuclear genome. mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation.

Figure 2

Schematic model of the mitochondrial response to oxidative stress. Oxidative stress, including reactive oxygen species (ROS) and reactive nitrogen species, induces mitochondrial DNA (mtDNA) mutation and cellular dyshomeostasis. Oxidative stress and mtDNA mutation can lead to: (1) dysfunction of mitochondrial fusion and/or fission dynamics, (2) recruitment of the NLRP3 inflammasome and (3) mitochondria-associated endoplasmic reticulum membrane (MAM) alteration.

Figure 3

Mitochondrial defense strategies. Mitochondria have internal defense mechanisms, such as the unfolded protein response (UPR) and mitophagy. However, excessive reactive oxygen species (ROS) generation and mitochondrial DNA (mtDNA) mutation result in the inhibition of these systems. Mitochondria-specific antioxidants and mitochondria-targeted genomic modulation can reduce oxidative stress-induced mtDNA mutation and mitochondrial dysfunction.