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Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

Ross JM, Olson L, Coppotelli G - Int J Mol Sci (2015)

Bottom Line: Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases.Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases.Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm 171 77, Sweden. jaime.ross@ki.se.

ABSTRACT
Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.

No MeSH data available.


Related in: MedlinePlus

UPS and mitochondrial cross-talk. Several factors, including genes, environment, age, diseases, diet, and exercise can either positively or negatively affect UPS activity and mitochondrial function. Impairment of one of the two systems can then drive the malfunctioning of the other and result in a vicious cycle. A decrease in cellular ATP levels and an increase in ROS production can impair proteasomal function by affecting protein ubiquitination and proteasome assembly and stability, while a decrease in UPS activity could impair mitochondrial function by affecting mitochondrial dynamics, mitophagy, and the removal of damaged mitochondrial proteins.
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ijms-16-19458-f002: UPS and mitochondrial cross-talk. Several factors, including genes, environment, age, diseases, diet, and exercise can either positively or negatively affect UPS activity and mitochondrial function. Impairment of one of the two systems can then drive the malfunctioning of the other and result in a vicious cycle. A decrease in cellular ATP levels and an increase in ROS production can impair proteasomal function by affecting protein ubiquitination and proteasome assembly and stability, while a decrease in UPS activity could impair mitochondrial function by affecting mitochondrial dynamics, mitophagy, and the removal of damaged mitochondrial proteins.

Mentions: ROS is a group of potentially harmful compounds that can damage all cellular components, including proteins, DNA, and lipids. Oxidation can affect protein structure, thus impairing function, and might also render proteins prone to aggregation, which could result in toxicity. The complete disassembly of the proteasome, resulting in an increase of 20S CPs, could be a protective mechanism to counteract a temporary rise in oxidative damage. It has been shown that 20S CP is more resistant to oxidative damage, compared to 19S RP, and is able to bind and degrade mis-folded oxidized proteins without the need for ubiquitination and ATP expenditure [84,85,86]. Thus, a temporary disassembly of the proteasome holoenzyme together with an up-regulation of an antioxidant stress response, heat shock proteins, and autophagic flux could be seen as part of a cellular strategy to counteract an acute increase in oxidative damage. Hence, through the uncapping of the 20S CP, cells might redirect the degradation capability of the proteasome from the removal of ubiquitinated substrates to the removal of oxidized proteins. However, since oxidative stress is a hallmark of ageing and age-related diseases, chronic exposure to oxidative stress could result in proteasome disassembly, which could further aggravate these conditions (Figure 2).


Mitochondrial and Ubiquitin Proteasome System Dysfunction in Ageing and Disease: Two Sides of the Same Coin?

Ross JM, Olson L, Coppotelli G - Int J Mol Sci (2015)

UPS and mitochondrial cross-talk. Several factors, including genes, environment, age, diseases, diet, and exercise can either positively or negatively affect UPS activity and mitochondrial function. Impairment of one of the two systems can then drive the malfunctioning of the other and result in a vicious cycle. A decrease in cellular ATP levels and an increase in ROS production can impair proteasomal function by affecting protein ubiquitination and proteasome assembly and stability, while a decrease in UPS activity could impair mitochondrial function by affecting mitochondrial dynamics, mitophagy, and the removal of damaged mitochondrial proteins.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581307&req=5

ijms-16-19458-f002: UPS and mitochondrial cross-talk. Several factors, including genes, environment, age, diseases, diet, and exercise can either positively or negatively affect UPS activity and mitochondrial function. Impairment of one of the two systems can then drive the malfunctioning of the other and result in a vicious cycle. A decrease in cellular ATP levels and an increase in ROS production can impair proteasomal function by affecting protein ubiquitination and proteasome assembly and stability, while a decrease in UPS activity could impair mitochondrial function by affecting mitochondrial dynamics, mitophagy, and the removal of damaged mitochondrial proteins.
Mentions: ROS is a group of potentially harmful compounds that can damage all cellular components, including proteins, DNA, and lipids. Oxidation can affect protein structure, thus impairing function, and might also render proteins prone to aggregation, which could result in toxicity. The complete disassembly of the proteasome, resulting in an increase of 20S CPs, could be a protective mechanism to counteract a temporary rise in oxidative damage. It has been shown that 20S CP is more resistant to oxidative damage, compared to 19S RP, and is able to bind and degrade mis-folded oxidized proteins without the need for ubiquitination and ATP expenditure [84,85,86]. Thus, a temporary disassembly of the proteasome holoenzyme together with an up-regulation of an antioxidant stress response, heat shock proteins, and autophagic flux could be seen as part of a cellular strategy to counteract an acute increase in oxidative damage. Hence, through the uncapping of the 20S CP, cells might redirect the degradation capability of the proteasome from the removal of ubiquitinated substrates to the removal of oxidized proteins. However, since oxidative stress is a hallmark of ageing and age-related diseases, chronic exposure to oxidative stress could result in proteasome disassembly, which could further aggravate these conditions (Figure 2).

Bottom Line: Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases.Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases.Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Karolinska Institutet, Retzius väg 8, Stockholm 171 77, Sweden. jaime.ross@ki.se.

ABSTRACT
Mitochondrial dysfunction and impairment of the ubiquitin proteasome system have been described as two hallmarks of the ageing process. Additionally, both systems have been implicated in the etiopathogenesis of many age-related diseases, particularly neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. Interestingly, these two systems are closely interconnected, with the ubiquitin proteasome system maintaining mitochondrial homeostasis by regulating organelle dynamics, the proteome, and mitophagy, and mitochondrial dysfunction impairing cellular protein homeostasis by oxidative damage. Here, we review the current literature and argue that the interplay of the two systems should be considered in order to better understand the cellular dysfunction observed in ageing and age-related diseases. Such an approach may provide valuable insights into molecular mechanisms underlying the ageing process, and further discovery of treatments to counteract ageing and its associated diseases. Furthermore, we provide a hypothetical model for the heterogeneity described among individuals during ageing.

No MeSH data available.


Related in: MedlinePlus