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Wu Y.-T.,Mackay Medical College | Wu S.-B.,Mackay Medical College | Wei Y.-H.,Mackay Medical College | Wei Y.-H.,National Yang Ming University
Free Radical Research | Year: 2014

In addition to serving as the power house of mammalian cells, mitochondria are crucial for the maintenance of cellular homeostasis in response to physiological or environmental changes. Several lines of evidence suggest that posttranslational modification (PTM) of proteins plays a pivotal role in the regulation of the bioenergetic function of mitochondria. Among them, reversible lysine acetylation of mitochondrial proteins has been established as one of the key mechanisms in cellular response to energy demand by modulating the flux of a number of key metabolic pathways. In this article, we focus on the role of Sirt3-mediated deacetylation in: (1) flexibility of energy metabolism, (2) activation of antioxidant defense, and (3) maintenance of cellular redox status in response to dietary challenge and oxidative stress. We suggest that oxidative stress-elicited down-regulation of Sirt3 plays a role in the pathophysiology of diabetes, cardiac hypotrophy, mitochondrial diseases, and age-related diseases. Besides, the physiological role of newly identified lysine acylation mediated by Sirt5 and its biochemical effects on oxidative metabolism are also discussed. Moreover, we have integrated the regulatory function of several protein kinases that are involved in the phosphorylation of mitochondrial enzymes during oxidative stress. Finally, the functional consequence of the synergistic regulation through diverse protein modifications is emphasized on the maintenance of the bioenergetic homeostasis and metabolic adaptation of the animal and human cells. Together, we have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress. © 2014 Informa UK, Ltd.

Chen C.-T.,National Yang Ming University | Hsu S.-H.,National Yang Ming University | Wei Y.-H.,National Yang Ming University | Wei Y.-H.,Mackay Medical College
Biochimica et Biophysica Acta - General Subjects | Year: 2012

Background: The self-renewal ability and pluripotent differentiation potential of stem cells hold great promise for regenerative medicine. Many studies focus on the lineage-specific differentiation and expansion of stem cells, but little is known about the regulation of glycolysis and mitochondrial biogenesis and function during these processes. Recent studies have demonstrated a strong correlation between cellular metabolism and the pluripotency and differentiation potential of stem cells, which indicates the importance of bioenergetic function in the regulation of stem cell physiology. Scope of review: We summarize recent findings in the control of stem cell competence through the regulation of bioenergetic function in embryonic, hematopoietic, mesenchymal, and induced pluripotent stem cells, and discuss the up-to-date understanding of the molecular mechanisms involved in these biological processes. Major conclusions: It is believed that the metabolic signatures are highly correlated with the stemness status (high glycolytic flux) and differentiation potential (mitochondrial function) of stem cells. Besides, mitochondrial rejuvenation has been observed to participate in the reprogramming process. General significance: Understanding the metabolic regulation of stem cells will have great value in the characterization and isolation of stem cells with better differentiation potential. It also provides novel strategies of metabolic manipulation to increase the efficiency of cellular reprogramming. This article is part of a Special Issue entitled Biochemistry of Mitochondria, Life and Intervention 2010. © 2011 Elsevier B.V.

Lee H.-C.,National Yang Ming University | Wei Y.-H.,National Yang Ming University | Wei Y.-H.,Mackay Medical College
Advances in Experimental Medicine and Biology | Year: 2012

Aging is a degenerative process that is associated with progressive accumulation of deleterious changes with time, reduction of physiological function and increase in the chance of disease and death. Studies in several species reveal a wide spectrum of alterations in mitochondria and mitochondrial DNA (mtDNA) with aging, including (1) increased disorganization of mitochondrial structure, (2) decline in mitochondrial oxidative phosphorylation (OXPHOS) function, (3) accumulation of mtDNA mutation, (4) increased mitochondrial production of reactive oxygen species (ROS) and (5) increased extent of oxidative damage to DNA, proteins, and lipids. In this chapter, we outline the common alterations in mitochondria of the aging tissues and recent advances in understanding the role of mitochondrial H 2O 2 production and mtDNA mutation in the aging process and lifespan determination. In addition, we discuss the effect of caloric restriction on age-associated mitochondrial changes and its role in longevity. Taking these findings together, we suggest that decline in mitochondrial energy metabolism, enhanced mitochondrial oxidative stress, and accumulation of mtDNA mutations are important contributors to human aging. © 2012 Springer Science+Business Media B.V.

Wang C.-H.,National Yang Ming University | Wang C.-C.,National Yang Ming University | Huang H.-C.,National Yang Ming University | Wei Y.-H.,National Yang Ming University | Wei Y.-H.,Mackay Medical College
FEBS Journal | Year: 2013

Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome. © 2012 The Authors Journal compilation © 2012 FEBS.

Wu Y.-T.,National Yang Ming University | Lee H.-C.,National Yang Ming University | Liao C.-C.,National Yang Ming University | Wei Y.-H.,National Yang Ming University | Wei Y.-H.,Mackay Medical College
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Sirt3, a mitochondrial NAD+-dependent deacetylase, is regarded as a potential regulator in cellular metabolism. However, the role of Sirt3 in the regulation of mitochondrial FoF1ATPase and the linkage to mitochondrial diseases is unclear. In this study, we demonstrated a role of Sirt3 in the regulation of FoF1ATPase activity in human cells. Knockdown of Sirt3 in 143B cells by shRNA transfection caused increased acetylation levels of the α and OSCP subunits of FoF1ATPase. We showed that Sirt3 physically interacted with the OSCP and led to its subsequent deacetylation. By incubation of mitochondria with the purified Sirt3 protein, Sirt3 could regulate FoF1ATPase activity through its deacetylase activity. Moreover, suppression of Sirt3 reduced the FoF1ATPase activity, consequently decreased the intracellular ATP level, diminished the capacity of mitochondrial respiration, and compromised metabolic adaptability of 143B cells to the use of galactose as the energy source. In human cells harboring ≅85% of mtDNA with 4977bp deletion, we showed that oxidative stress induced a reduction of Sirt3 expression, and an increased acetylation of the OSCP subunit of FoF1ATPase. Importantly, the expression of Sirt3 was also decreased in the skin fibroblasts from patients with CPEO syndrome. We further demonstrated that oxidative stress induced by 5-10μM of menadione impaired the Sirt3-mediated deacetylation and activation on FoF1ATPase activity through decreasing the protein level of Sirt3. Our findings suggest that increased intracellular ROS levels might modulate the expression of Sirt3 which deacetylates and activates FoF1ATPase in human cells with mitochondrial dysfunction caused by a pathogenic mtDNA mutation. © 2012 Elsevier B.V.

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