Circulation Journal Official Journal of the Japanese Circulation Society, Oct 25, 2011
Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maint... more Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.
Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maint... more Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.
The peroxisome proliferator-activated receptor (PPAR) transcription factors are nuclear receptors... more The peroxisome proliferator-activated receptor (PPAR) transcription factors are nuclear receptors initially identified for their key role in regulating metabolic processes. Recent studies designed to identify the role of PPARalpha, -beta, and -gamma in vivo uncovered extrametabolic roles that may be less well known in the heart. In this review, we describe what is known about these extrametabolic roles of PPARs, including regulation of cardiac inflammation, extracellular matrix remodeling, oxidative stress, and regulation of cardiac hypertrophy. Lastly, we discuss the emerging role of PPARs in cell cycle regulation and angiogenesis in noncardiac systems that may be applicable to heart biology. Although this review primarily discusses the extrametabolic role of PPARalpha, the most studied PPAR isoform in the heart, we highlight where possible what is known about the unique and overlapping roles of the PPAR isoforms in terms of metabolic function.
One of the master regulators of both glucose and lipid cellular metabolism is 5&a... more One of the master regulators of both glucose and lipid cellular metabolism is 5'-AMP-activated protein kinase (AMPK). As a metabolic pivot that dynamically responds to shifts in nutrient availability and stress, AMPK dysregulation is implicated in the underlying molecular pathology of a variety of diseases, including cardiovascular diseases, diabetes, cancer, neurological diseases, and aging. Although the regulation of AMPK enzymatic activity by upstream kinases is an active area of research, less is known about regulation of AMPK protein stability and activity by components of the ubiquitin-proteasome system (UPS), the cellular machinery responsible for both the recognition and degradation of proteins. Furthermore, there is growing evidence that AMPK regulates overall proteasome activity and individual components of the UPS. This review serves to identify the current understanding of the interplay between AMPK and the UPS and to promote further exploration of the relationship between these regulators of energy use and amino acid availability within the cell.
Circulation Journal Official Journal of the Japanese Circulation Society, Oct 25, 2011
Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maint... more Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.
Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maint... more Mitochondria are dynamic organelles that undergo a constant cycle of division and fusion to maintain their function. The process of mitochondrial fusion has the effect of mixing their content, allowing complementation of protein components, mtDNA repair, and distribution of metabolic intermediates. Fission, on the other hand, enables mitochondria to increase in number and capacity, and to segregate mitochondria for autophagy by the lysosome ("mitophagy"). Disruption of these protein quality control mechanisms has recently been identified in multiple cardiac diseases, including cardiac hypertrophy, heart failure, dilated cardiomyopathy, and ischemic heart disease, and is intimately tied to mitochondrial control of apoptosis. Proteins that regulate mitochondrial fusion and fission have been discovered, including Mfn1, Mfn2, and Opa1 (fusion) and Drp1 and Fis1 (fission). In this review, we discuss how these proteins are regulated by post-translational modification with ubiquitin and SUMO (small ubiquitin-like modifier). We then present what is known about the ubiquitin and SUMO ligases that regulate these post-translational modifications and regulation of mitochondrial fusion and fission, exploring their potential as therapeutic targets of cardiac disease.
The peroxisome proliferator-activated receptor (PPAR) transcription factors are nuclear receptors... more The peroxisome proliferator-activated receptor (PPAR) transcription factors are nuclear receptors initially identified for their key role in regulating metabolic processes. Recent studies designed to identify the role of PPARalpha, -beta, and -gamma in vivo uncovered extrametabolic roles that may be less well known in the heart. In this review, we describe what is known about these extrametabolic roles of PPARs, including regulation of cardiac inflammation, extracellular matrix remodeling, oxidative stress, and regulation of cardiac hypertrophy. Lastly, we discuss the emerging role of PPARs in cell cycle regulation and angiogenesis in noncardiac systems that may be applicable to heart biology. Although this review primarily discusses the extrametabolic role of PPARalpha, the most studied PPAR isoform in the heart, we highlight where possible what is known about the unique and overlapping roles of the PPAR isoforms in terms of metabolic function.
One of the master regulators of both glucose and lipid cellular metabolism is 5&a... more One of the master regulators of both glucose and lipid cellular metabolism is 5'-AMP-activated protein kinase (AMPK). As a metabolic pivot that dynamically responds to shifts in nutrient availability and stress, AMPK dysregulation is implicated in the underlying molecular pathology of a variety of diseases, including cardiovascular diseases, diabetes, cancer, neurological diseases, and aging. Although the regulation of AMPK enzymatic activity by upstream kinases is an active area of research, less is known about regulation of AMPK protein stability and activity by components of the ubiquitin-proteasome system (UPS), the cellular machinery responsible for both the recognition and degradation of proteins. Furthermore, there is growing evidence that AMPK regulates overall proteasome activity and individual components of the UPS. This review serves to identify the current understanding of the interplay between AMPK and the UPS and to promote further exploration of the relationship between these regulators of energy use and amino acid availability within the cell.
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