Mitochondrial protein quality control: implications in ageing.
ABSTRACT Mitochondria represent both a major source for reactive oxygen species (ROS) production and a target for oxidative macromolecular damage. Increased production of ROS and accumulation of oxidized proteins have been associated with cellular ageing. Protein quality control, also referred as protein maintenance, is very important for the elimination of oxidized proteins through degradation and repair. Chaperone proteins have been implicated in refolding of misfolded proteins while oxidized protein repair is limited to the catalyzed reduction of certain oxidation products of the sulfur-containing amino acids, cysteine and methionine, by specific enzymatic systems. In the mitochondria, oxidation of methionine residues within proteins can be catalytically reversed by the methionine sulfoxide reductases, an ubiquitous enzymatic system that has been implicated both in ageing and protection against oxidative stress. Irreversibly oxidized proteins are targeted to degradation by mitochondrial matrix proteolytic systems such as the Lon protease. The ATP-stimulated Lon protease is believed to play a crucial role in the degradation of oxidized proteins within the mitochondria and age-related declines in the activity and/or expression of this proteolytic system have been previously reported. Age-related impairment of mitochondrial protein maintenance may therefore contribute to the age-associated build-up of oxidized proteins and impairment of mitochondrial redox homeostasis.
- [show abstract] [hide abstract]
ABSTRACT: We investigated the role of methionine sulfoxide reductases (Msrs) in oxidant-stress-induced cell death in retinal pigmented epithelial (RPE) cells. In RPE cells exposed to varying doses of H(2)O(2), gene expression of MsrA and hCBS-1 (the human analog of MsrB2) increased in a dose-dependent and time-dependent manner with maximal increase with 150 microM H(2)O(2) in 24h. H(2)O(2) treatment resulted in the generation of reactive oxygen species and activation of caspase 3. Confocal microscopic and protein analysis showed an increase in MsrA expression in cytosol and mitochondria. Silencing of MsrA resulted in caspase 3 induction and accentuated cell death from H(2)O(2). Focal, strong immunoreactivity for MsrA was observed in sub-RPE macular drusen from patients with age-related macular degeneration. In summary, our data show that MsrA and hCBS-1 are up-regulated in oxidative stress to counteract injury to RPE.Biochemical and Biophysical Research Communications 09/2005; 334(1):245-53. · 2.41 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Damage to cellular components by reactive oxygen species is believed to be an important factor contributing to the aging process. Likewise, the progressive failure of maintenance and repair is believed to be a major cause of biological aging. Cellular aging is characterized by the accumulation of oxidatively modified proteins, a process that results, at least in part, from impaired protein turnover. Indeed, oxidized protein buildup with age may be due to increased protein damage, decreased elimination of oxidized protein (i.e., repair and degradation), or a combination of both mechanisms. Since the proteasome has been implicated in both general protein turnover and the removal of oxidized protein, the fate of the proteasome during aging has recently received considerable attention, and evidence has been provided for impaired proteasome function with age in different cellular systems. The present review will mainly address age-related changes in proteasome structure and function in relation to the impact of oxidative stress on the proteasome and the accumulation of oxidized protein. Knowledge of molecular mechanisms involved in the decline of proteasome function during aging and in oxidative stress is expected to provide new insight that will be useful in defining antiaging strategies aimed at preserving this critical function.Antioxidants and Redox Signaling 01/2006; 8(1-2):205-16. · 7.19 Impact Factor
Article: AAA proteins.[show abstract] [hide abstract]
ABSTRACT: AAA proteins have entered the molecular realm after being known primarily for their wide range of different functions. Structural studies have highlighted the organization of their constituent ATPase domains and indicate that hexamerization in combination with unfoldase activity is a common underlying feature of this ubiquitous protein family.Current Opinion in Structural Biology 01/2003; 12(6):746-53. · 8.74 Impact Factor