The role of mitochondrial ROS in the aging brain

Abstract

The brain is the most complex human organ, consuming more energy than any other tissue in proportion to its size. It relies heavily on mitochondria to produce energy and is made up of mitotic and postmitotic cells that need to closely coordinate their metabolism to maintain essential bodily functions. During aging, damaged mitochondria that produce less ATP and more reactive oxygen species (ROS) accumulate. The current consensus is that ROS cause oxidative stress, damaging mitochondria and resulting in an energetic crisis that triggers neurodegenerative diseases and accelerates aging. However, in model organisms, increasing mitochondrial ROS (mtROS) in the brain extends lifespan, suggesting that ROS may participate in signaling that protects the brain. Here, we summarize the mechanisms by which mtROS are produced at the molecular level, how different brain cells and regions produce different amounts of mtROS, and how mtROS levels change during aging. Finally, we critically discuss the possible roles of ROS in aging as signaling molecules and damaging agents, addressing whether age-associated increases in mtROS are a cause or a consequence of aging.

Aberrant cardiolipin metabolism is associated with cognitive deficiency and hippocampal alteration in tafazzin knockdown mice

“…Alternatively, microglial activation maybe due to their own aberrant level of ROS. This process however is typically supported by an inflammatory response, which remained similar (GFAP) between the genotypes 61 .…”

“…While TAZ-deficiency in the brain did not result in supercomplex dissociation, the elevated basal respiratory activity combined with a significant increase in the “free” monomeric form of complex I provides a basis for excessive ROS. It is established that high levels of mitochondrial ROS and the subsequent oxidative stress can cause cell death via apoptosis or necrosis in the brain 61 . In mouse brain studies, cognitive dysfunction has correlated with the level of oxidative damage 62 .…”

“…In mouse brain studies, cognitive dysfunction has correlated with the level of oxidative damage 62 . Interestingly, CAI neurons in the hippocampus, which were significantly deranged in the TAZ kd mouse, are among the most sensitive to oxidative stress 61 . Elevated levels of neuronal ROS and/or peroxidized lipid metabolites may additionally promote microglial activation 57 .…”

Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation

“…These aggregates in turn may further impair the proteasome activity (Grune et al, 2004), thus creating a negative feedback loop. Other key 10 pathways implicated in aging are affected by this loss of stoichiometry: in particular, alterations of respiratory chain complexes (particularly Complex IV and V) might contribute to their decreased activity and increased ROS production in old brain (Stefanatos and Sanz, 2018), and changes in multiple spliceosome complexes might underlie previously observed qualitative changes of splicing (Ori et al, 2015). More detailed mechanistic studies are needed to 15 demonstrate that the alterations that we have described are sufficient to impair the function of these protein complexes during aging.…”

Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Non-coding RNAs, and Forkhead Transcription Factors

“…It is expected that the number of elderly individuals in large developing countries such as India and China also will increase from five percent to ten percent over the next several decades (4, 5). There are a number of reasons that may account for the increased lifespan, but improvements in effective treatments for multiple disorders (6–10) and broader access to preventive care are believed to have contributed to the increased life span of the world’s population. For NCDs, greater than ten percent of the population under sixty years of age is affected in high-income countries (1).…”