Abstract
Elevated concentration of homocysteine (Hcy) in the blood plasma, hyperhomocysteinemia (HHcy), has been implicated in various disorders, including cardiovascular and neurodegenerative diseases. Accumulating evidence indicates that pathophysiology of these diseases is linked with mitochondrial dysfunction. In this review, we discuss the current knowledge concerning the effects of HHcy on mitochondrial homeostasis, including energy metabolism, mitochondrial apoptotic pathway, and mitochondrial dynamics. The recent studies suggest that the interaction between Hcy and mitochondria is complex, and reactive oxygen species (ROS) are possible mediators of Hcy effects. We focus on mechanisms contributing to HHcy-associated oxidative stress, such as sources of ROS generation and alterations in antioxidant defense resulting from altered gene expression and post-translational modifications of proteins. Moreover, we discuss some recent findings suggesting that HHcy may have beneficial effects on mitochondrial ROS homeostasis and antioxidant defense. A better understanding of complex mechanisms through which Hcy affects mitochondrial functions could contribute to the development of more specific therapeutic strategies targeted at HHcy-associated disorders.
Highlights
Homocysteine (Hcy) is a sulfur-containing amino acid (Figure 1) formed during metabolism of methionine, an essential amino acid derived from dietary proteins
In cells incubated with 2.7 mmol/L Hcy, further decreases in ∆Ψm and ATP content occurred, leading to apoptosis and necrosis
Upregulation of pro-apoptotic and downregulation of anti-apoptotic proteins, release of cytochrome c, or activation of caspase-9 and its downstream caspase-3 was shown in different cell lines, including hippocampal neuronal cells [78,101,102], cerebellar granule cells [103], neuroblastoma cells [57,104,105], brain endothelial cells [86,106], human umbilical vein endothelial cells (HUVECs) [69,72,73,107,108,109], heart microvascular endothelial cells [110], aortic endothelial cells [111], as well as in animal models [112,113]
Summary
Homocysteine (Hcy) is a sulfur-containing amino acid (Figure 1) formed during metabolism of methionine, an essential amino acid derived from dietary proteins. A casual factor for Alzheimer’s disease; senile, disease vascular, and other dementias [5]; Parkinson’s disease cardiovascular disease.(CVD) Hcy factor in these other diseases, the related disease [7];large and heart failure might be aof casual forand disease. Hcy can change structure and function of proteins by binding to their lysine or cysteine. S-homocysteinylation, and function proteins by binding to their lysine or are cysteine these post-translational respectively Processes in the brain and heart are critically dependent on mitochondrial and a large body of evidence suggests that mitochondrial disorders play an important role infunction, the pathogenesis of body of evidence suggests that mitochondrial disorders play an important role in the pathogenesis the above-mentioned neurodegenerative and cardiovascular diseases [22]. Of hyperhomocysteinemia in mitochondrial dysfunction and focus on ROS as of alteredthe cellular possible mediators of altered cellular functions
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