Mitochondrial DNA damage and reactive oxygen species in neurodegenerative disease

Abstract

Mitochondria are essential organelles within the cell where most ATP is produced through oxidative phosphorylation (OXPHOS). A subset of the genes needed for this process are encoded by the mitochondrial DNA (mtDNA). One consequence of OXPHOS is the production of mitochondrial reactive oxygen species (ROS), whose role in mediating cellular damage, particularly in damaging mtDNA during ageing, has been controversial. There are subsets of neurons that appear to be more sensitive to ROS-induced damage, and mitochondrial dysfunction has been associated with several neurodegenerative disorders. In this review, we will discuss the current knowledge in the field of mtDNA and neurodegeneration, the debate about ROS as a pathological or beneficial contributor to neuronal function, bona fide mtDNA diseases, and insights from mouse models of mtDNA defects affecting the central nervous system.

Maternal exposure causes mitochondrial dysfunction in brain, liver, and heart of mouse fetus: An explanation for perfluorooctanoic acid induced abortion and developmental toxicity

“…Mitochondrial dysfunction is a pathologic mechanism that results in toxicities in tissues especially in the liver, heart, and brain. caused the release of cytochrome c. In the brain mitochondria, PFOA showed similar effects of on ROS generation, activity of mitochondrial complexes I and III, MMP, mitochondrial swelling, ATP level and release of cytochrome C. 33 In our study, we showed similar effect on isolated mitochondria obtained for liver, brain and heart of the mouse embryos but there is no similar effect on placenta. Moreover, a recent study worked by Choi et al showed that PFOA induces MMP collapse, cardiolipin peroxidation, cytochrome c release, and decreased ATP levels, which in turn induced apoptosis or necrosis in MC3T3-E1 osteoblast cells.…”

“…Mashayekhi et al indicated that PFOA has adverse effect on some vital biochemical functions of mitochondria. In liver mitochondria, PFOA increased ROS generation due to interfering with the activities of complexes I, II, and III in mitochondrial respiratory chain; caused MMP collapse and mitochondrial swelling; decreased ATP level; and caused the release of cytochrome c. In the brain mitochondria, PFOA showed similar effects of on ROS generation, activity of mitochondrial complexes I and III, MMP, mitochondrial swelling, ATP level and release of cytochrome C . In our study, we showed similar effect on isolated mitochondria obtained for liver, brain and heart of the mouse embryos but there is no similar effect on placenta.…”

“…One of the main products of oxidative phosphorylation in mitochondria is ROS. The neurons are more sensitive to ROS‐induced damage, particularly mitochondrial DNA dysfunction that is associated with several neurodegenerative disorders . Our results in brain isolated mitochondria indicated that PFOA increased mitochondrial ROS, mitochondrial collapse and mitochondrial swelling.…”

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…Many prevalent and rare neurodegenerative disorders have been associated with mitochondrial deficiencies, which affect central as well as peripheral parts of the nervous system (Nunnari & Suomalainen, 2012;Kawamata & Manfredi, 2017;Viscomi & Zeviani, 2017;Nissanka & Moraes, 2018). Mitochondria are central metabolic organelles and therefore of pivotal importance for neuronal survival.…”

Lysosomal dysfunction impairs mitochondrial quality control and predicts neurodegeneration in TBCKE

“…If mtDNA copy number reduction is not due to reduced amount of mitochondria per cell, an alternative scenario is reduced amount of mtDNA per mitochondria. Reactive Oxygen Species (ROS) generated in the mitochondria are known to induce mtDNA damage (Nissanka & Moraes, 2018). Therefore, we next assayed ROS levels at baseline conditions using CellROX in controls vs TCBK (mild and severe) fibroblasts.…”