p66Shc Aging Protein in Control of Fibroblasts Cell Fate

Reactive oxygen species (ROS) are wieldy accepted as one of the main factors of the aging process. These highly reactive compounds modify nucleic acids, proteins and lipids and affect the functionality of mitochondria in the first case and ultimately of the cell. Any agent or genetic modification that affects ROS production and detoxification can be expected to influence longevity. On the other hand, genetic manipulations leading to increased longevity can be expected to involve cellular changes that affect ROS metabolism. The 66-kDa isoform of the growth factor adaptor Shc (p66Shc) has been recognized as a relevant factor to the oxygen radical theory of aging. The most recent data indicate that p66Shc protein regulates life span in mammals and its phosphorylation on serine 36 is important for the initiation of cell death upon oxidative stress. Moreover, there is strong evidence that apart from aging, p66Shc may be implicated in many oxidative stress-associated pathologies, such as diabetes, mitochondrial and neurodegenerative disorders and tumorigenesis. This article summarizes recent knowledge about the role of p66Shc in aging and senescence and how this protein can influence ROS production and detoxification, focusing on studies performed on skin and skin fibroblasts

Oxidative stress-dependent p66Shc phosphorylation in skin fibroblasts of children with mitochondrial disorders.

p66Shc, the growth factor adaptor protein, can have a substantial impact on mitochondrial metabolism through regulation of cellular response to oxidative stress. We investigated relationships between the extent of p66Shc phosphorylation at Ser36, mitochondrial dysfunctions and an antioxidant defense reactions in fibroblasts derived from five patients with various mitochondrial disorders (two with mitochondrial DNA mutations and three with methylglutaconic aciduria and genetic defects localized, most probably, in nuclear genes). We found that in all these fibroblasts, the extent of p66Shc phosphorylation at Ser36 was significantly increased. This correlated with a substantially decreased level of mitochondrial superoxide dismutase (SOD2) in these cells. This suggest that SOD2 is under control of the Ser36 phosphorylation status of p66Shc protein. As a consequence, an intracellular oxidative stress and accumulation of damages caused by oxygen free radicals are observed in the cells

Cardiac mitochondrial dysfunction during hyperglycemia-The role of oxidative stress and p66Shc signaling

Diabetes mellitus is a chronic disease caused by a deficiency in the production of insulin and/or by the effects of insulin resistance. Insulin deficiency leads to hyperglycemia which is the major initiator of diabetic cardiovascular complications escalating with time and driven by many complex biochemical and molecular processes. Four hypotheses, which propose mechanisms of diabetes-associated pathophysiology, are currently considered. Cardiovascular impairment may be caused by an increase in polyol pathway flux, by intracellular advanced glycation end-products formation or increased flux through the hexosamine pathway. The latter of these mechanisms involves activation of the protein kinase C. Cellular and mitochondrial metabolism alterations observed in the course of diabetes are partially associated with an excessive production of reactive oxygen species (ROS). Among many processes and factors involved in ROS production, the 66 kDa isoform of the growth factor adaptor shc (p66Shc protein) is of particular interest. This protein plays a key role in the control of mitochondria-dependent oxidative balance thus it involvement in diabetic complications and other oxidative stress based pathologies is recently intensively studied. In this review we summarize the current understanding of hyperglycemia induced cardiac mitochondrial dysfunction with an emphasis on the oxidative stress and p66Shc protein. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy. © 2012 Elsevier Ltd