nemoci-sympt/METABOLISMUS/mitochondrie/metabolizmus/jednotlive-proteiny-abc
Calcium- and second messenger-dependent regulation of PGC-1a expression
- Increased contractile activity
CaN - calcineurin
- Controls the expression of PGC-1a in muscle
- calcium-signalling pathway
- Increased mitochondrial content
- Loss of calcineurin in heart
- Impaired mitochondrial electron transport
- High levels of superoxide production
- CaN and CaMK
- Activate distinct but overlapping metabolic gene regulatory programs
CaN
- Activates the mouse PPARa promoter
- FAO genes are selectively activated by CaN
- CaN-mediated PGC-1a promoter activation dependent on
- Myocyte enhancer factor-2 (MEF2) activity
- Histone deacetylases (HDACs) [8]
- Signal-resistant form of HDAC in mouse heart
- Loss of mitochondria
- Changes in their morphology [8]
MEF2
- Stimulated by CaN signalling
- Binds to the PGC-1a promoter
- Activates it
- Predominantly when co-activated by itself
- Deletion of MEF2A in mice
- Perturbation of mitochondrial structure
- Significant loss of mitochondria
CaMK
- Activation of PGC-1a expression
- Requires the cAMP response element-binding protein (CREB)
Transducer of regulated CREB-binding protein (TORC)
- May enhance CREB-dependent PGC-1a transcription
CREB
- Strong positive correlation
- CREB activation with PGC-1a expression
- mitochondrial respiratory rate
- protein content [8]
DrPp1
- Expression correlates with the
- PGC-1a content
- Calcineurin activation in human skeletal muscle
- Dephosphorylation of Drp1 by CaN
- Induces its translocation to mitochondria
- Triggering mitochondrial fission
Activation of the p38 mitogen-activated protein kinase(MAPK) pathway in skeletal muscle has been shown topromote PGC-1a expression. However, the cardiac mitochondriaof transgenic mice overexpressing the p38MAPKupstream kinase MAPK-kinase-6 (MKK6) have lower oxidativerespiration and decreased generation of reactive oxygenspecies,46 suggesting that p38MAPK is involved in the negativeregulation of mitochondrial biogenesis.Treatment of various cells with NO donors increases theirmtDNA content, and this is sensitive to removal of NO by NOscavengers.47 The effects of NO occur via increasedexpression of PGC-1a and its down-stream effectors, anddepend on the second messenger cGMP by activation of particulateguanylyl cyclase. Tissues of eNOS2/2 mice such asthe brain, liver, muscle and heart have a slightly decreasedcontent of some mitochondrial proteins.47 However, oxidativecapacity and mitochondrial enzymes are not alteredin hearts of eNOS2/2 mice, suggesting that eNOS is notinvolved in cardiac basal mitochondrial biogenesis.48However, eNOS may be necessary for the cardiac responseto stress, since caloric restriction involves an eNOSdependentincrease in cardiac mitochondrial biogenesis.493.2 Energy-dependent regulation of PGC-1aactivityIt has been proposed that the phylogenetically conservedAMP-dependent serine/threonine protein kinase (AMPK)plays a role in skeletal muscle-induced mitochondrial biogenesis.PGC-1a is induced by exercise and by chemical activationof AMPK in skeletal muscle (for review see Reznickand Shulman50). Activation of AMPK and mitochondrial biogenesisin muscle in response to chronic energydeprivation is diminished in AMPKa2-kinase-dead mice,revealing the importance of AMPK in this response.51Indeed, cardiac mitochondrial respiration is altered inmice lacking the main catalytic subunit of cardiac and skeletalmuscle AMPK (AMPKa22/2) by a mechanism thatinvolves decreased cardiolipin biosynthesis,52 suggestingthat AMPK is involved in cardiolipin biosynthesis. However,there are no changes in mitochondrial markers or PGC-1aexpression in the hearts of these mice.52,53Sirtuins are highly conserved NAD?-dependent deacetylasesrecently shown to control lifespan. Increased lifespanis associated with augmented mitochondrial oxidative phosphorylationand aerobic capacity. Resveratrol, a polyphenolthat was shown to extend lifespan, increases aerobic capacityin mice and induces expression of genes that encode proteinsinvolved in oxidative phosphorylation and mitochondrialbiogenesis. These effects occur via a SIRT-1-dependentincrease in PGC-1a expression in skeletal muscle andadipose tissue, although not in heart.54 Interestingly, caloricrestriction-induced mitochondrial biogenesis in heart isaccompanied by increased SIRT1 expression in wild-type butnot eNOS2/2 mice.49 These results again indicate that mitochondrialbiogenesis is strictly controlled in the heart.3.3 Hormonal control of PGC-1aThyroid hormones (TH) drastically alter the expression ofnuclear- and mitochondria-encoded genes in severaltissues. TH can control mammalian mitochondrial biogenesisthrough direct and indirect pathways. The direct pathwayinvolves the binding of TH receptors (TRa and b) on TRE recognitionsites on nuclear-encoded mitochondrial genes, andactivation of the mitochondrial genome via a truncated formof TRa called p43.55 However, of the nuclear genes necessaryfor the biogenesis of mitochondria, only a few responddirectly to thyroid hormone.11 An indirect pathway involvesthe control of PGC-1a expression, and activation of itsdownstream transcription cascade.56 However, the effectsof TH on mitochondrial content in the adult heart are notclear. Indeed, one study found that TH treatment of ratsincreased cardiac oxygen consumption, mitochondrial bioenergeticcapacity and expression of markers of mitochondrialbiogenesis such as PGC-1a and its transcriptioncascade.57 In contrast, other studies (including our ownunpublished results) found no change in PGC-1a myocardialexpression/activity with TH treatment.58 Interestingly, aninteraction between PGC-1a and thyroid hormone receptorshas been reported.59 Hypothyroidism induces a decrease inthe maximal oxidative capacity and expression/activity ofmitochondrial enzymes in cardiac muscle, which is independentof PGC-1a and its transcription cascade, suggestingthat there exists a unique mode of regulating mitochondrialrespiration by TH.60 Additionally, thyroid hormones controlcardiolipin biosynthesis and regulate the mitochondrial212 R. Ventura-Clapier et al.Downloaded from https://academic.oup.com/cardiovascres/article-abstract/79/2/208/271402by gueston 07 January 2018protein import machinery, thus providing another ways ofregulating mitochondrial function.9,61,62 [8]
Calcium- and second messenger-dependent regulation of PGC-1a expression
- Increased contractile activity
CaN - calcineurin
- Controls the expression of PGC-1a in muscle
- calcium-signalling pathway
- Increased mitochondrial content
- Loss of calcineurin in heart
- Impaired mitochondrial electron transport
- High levels of superoxide production
- CaN and CaMK
- Activate distinct but overlapping metabolic gene regulatory programs
CaN
- Activates the mouse PPARa promoter
- FAO genes are selectively activated by CaN
- CaN-mediated PGC-1a promoter activation dependent on
- Myocyte enhancer factor-2 (MEF2) activity
- Histone deacetylases (HDACs) [8]
- Signal-resistant form of HDAC in mouse heart
- Loss of mitochondria
- Changes in their morphology [8]
MEF2
- Stimulated by CaN signalling
- Binds to the PGC-1a promoter
- Activates it
- Predominantly when co-activated by itself
- Deletion of MEF2A in mice
- Perturbation of mitochondrial structure
- Significant loss of mitochondria
CaMK
- Activation of PGC-1a expression
- Requires the cAMP response element-binding protein (CREB)
Transducer of regulated CREB-binding protein (TORC)
- May enhance CREB-dependent PGC-1a transcription
CREB
- Strong positive correlation
- CREB activation with PGC-1a expression
- mitochondrial respiratory rate
- protein content [8]
DrPp1
- Expression correlates with the
- PGC-1a content
- Calcineurin activation in human skeletal muscle
- Dephosphorylation of Drp1 by CaN
- Induces its translocation to mitochondria
- Triggering mitochondrial fission
Activation of the p38 mitogen-activated protein kinase(MAPK) pathway in skeletal muscle has been shown topromote PGC-1a expression. However, the cardiac mitochondriaof transgenic mice overexpressing the p38MAPKupstream kinase MAPK-kinase-6 (MKK6) have lower oxidativerespiration and decreased generation of reactive oxygenspecies,46 suggesting that p38MAPK is involved in the negativeregulation of mitochondrial biogenesis.Treatment of various cells with NO donors increases theirmtDNA content, and this is sensitive to removal of NO by NOscavengers.47 The effects of NO occur via increasedexpression of PGC-1a and its down-stream effectors, anddepend on the second messenger cGMP by activation of particulateguanylyl cyclase. Tissues of eNOS2/2 mice such asthe brain, liver, muscle and heart have a slightly decreasedcontent of some mitochondrial proteins.47 However, oxidativecapacity and mitochondrial enzymes are not alteredin hearts of eNOS2/2 mice, suggesting that eNOS is notinvolved in cardiac basal mitochondrial biogenesis.48However, eNOS may be necessary for the cardiac responseto stress, since caloric restriction involves an eNOSdependentincrease in cardiac mitochondrial biogenesis.493.2 Energy-dependent regulation of PGC-1aactivityIt has been proposed that the phylogenetically conservedAMP-dependent serine/threonine protein kinase (AMPK)plays a role in skeletal muscle-induced mitochondrial biogenesis.PGC-1a is induced by exercise and by chemical activationof AMPK in skeletal muscle (for review see Reznickand Shulman50). Activation of AMPK and mitochondrial biogenesisin muscle in response to chronic energydeprivation is diminished in AMPKa2-kinase-dead mice,revealing the importance of AMPK in this response.51Indeed, cardiac mitochondrial respiration is altered inmice lacking the main catalytic subunit of cardiac and skeletalmuscle AMPK (AMPKa22/2) by a mechanism thatinvolves decreased cardiolipin biosynthesis,52 suggestingthat AMPK is involved in cardiolipin biosynthesis. However,there are no changes in mitochondrial markers or PGC-1aexpression in the hearts of these mice.52,53Sirtuins are highly conserved NAD?-dependent deacetylasesrecently shown to control lifespan. Increased lifespanis associated with augmented mitochondrial oxidative phosphorylationand aerobic capacity. Resveratrol, a polyphenolthat was shown to extend lifespan, increases aerobic capacityin mice and induces expression of genes that encode proteinsinvolved in oxidative phosphorylation and mitochondrialbiogenesis. These effects occur via a SIRT-1-dependentincrease in PGC-1a expression in skeletal muscle andadipose tissue, although not in heart.54 Interestingly, caloricrestriction-induced mitochondrial biogenesis in heart isaccompanied by increased SIRT1 expression in wild-type butnot eNOS2/2 mice.49 These results again indicate that mitochondrialbiogenesis is strictly controlled in the heart.3.3 Hormonal control of PGC-1aThyroid hormones (TH) drastically alter the expression ofnuclear- and mitochondria-encoded genes in severaltissues. TH can control mammalian mitochondrial biogenesisthrough direct and indirect pathways. The direct pathwayinvolves the binding of TH receptors (TRa and b) on TRE recognitionsites on nuclear-encoded mitochondrial genes, andactivation of the mitochondrial genome via a truncated formof TRa called p43.55 However, of the nuclear genes necessaryfor the biogenesis of mitochondria, only a few responddirectly to thyroid hormone.11 An indirect pathway involvesthe control of PGC-1a expression, and activation of itsdownstream transcription cascade.56 However, the effectsof TH on mitochondrial content in the adult heart are notclear. Indeed, one study found that TH treatment of ratsincreased cardiac oxygen consumption, mitochondrial bioenergeticcapacity and expression of markers of mitochondrialbiogenesis such as PGC-1a and its transcriptioncascade.57 In contrast, other studies (including our ownunpublished results) found no change in PGC-1a myocardialexpression/activity with TH treatment.58 Interestingly, aninteraction between PGC-1a and thyroid hormone receptorshas been reported.59 Hypothyroidism induces a decrease inthe maximal oxidative capacity and expression/activity ofmitochondrial enzymes in cardiac muscle, which is independentof PGC-1a and its transcription cascade, suggestingthat there exists a unique mode of regulating mitochondrialrespiration by TH.60 Additionally, thyroid hormones controlcardiolipin biosynthesis and regulate the mitochondrial212 R. Ventura-Clapier et al.Downloaded from https://academic.oup.com/cardiovascres/article-abstract/79/2/208/271402by gueston 07 January 2018protein import machinery, thus providing another ways ofregulating mitochondrial function.9,61,62 [8]
Cyclin-dependent kinases (CDKs)
- Involved in cell cycle and/or transcriptional control
cyclinT/Cdk9
- RNA polymerase kinase
- Involved in cardiac hypertrophy
- Suppresses the expression of many genes that encode mitochondrial proteins
- PGC-1a and its downstream effectors
Cdk7/cyclinH/me´nage-a`-trois-1 (MAT1) heterotrimer
- Activated in adult hearts
- By stress-dependent pathways for hypertrophic growth
- Ablation of MAT1
- Suppression of genes involved in energy metabolism
- PGC-1a and b genes [8]
Cyclin-dependent kinases (CDKs)
- Involved in cell cycle and/or transcriptional control
cyclinT/Cdk9
- RNA polymerase kinase
- Involved in cardiac hypertrophy
- Suppresses the expression of many genes that encode mitochondrial proteins
- PGC-1a and its downstream effectors
Cdk7/cyclinH/me´nage-a`-trois-1 (MAT1) heterotrimer
- Activated in adult hearts
- By stress-dependent pathways for hypertrophic growth
- Ablation of MAT1
- Suppression of genes involved in energy metabolism
- PGC-1a and b genes [8]
Activation of the p38 mitogen-activated protein kinase
(MAPK) pathway in skeletal muscle has been shown topromote PGC-1a expression. However, the cardiac mitochondriaof transgenic mice overexpressing the p38MAPKupstream kinase MAPK-kinase-6 (MKK6) have lower oxidativerespiration and decreased generation of reactive oxygenspecies,46 suggesting that p38MAPK is involved in the negativeregulation of mitochondrial biogenesis.Treatment of various cells with NO donors increases theirmtDNA content, and this is sensitive to removal of NO by NOscavengers.47 The effects of NO occur via increasedexpression of PGC-1a and its down-stream effectors, anddepend on the second messenger cGMP by activation of particulateguanylyl cyclase. Tissues of eNOS2/2 mice such asthe brain, liver, muscle and heart have a slightly decreasedcontent of some mitochondrial proteins.47 However, oxidativecapacity and mitochondrial enzymes are not alteredin hearts of eNOS2/2 mice, suggesting that eNOS is notinvolved in cardiac basal mitochondrial biogenesis.48However, eNOS may be necessary for the cardiac responseto stress, since caloric restriction involves an eNOSdependentincrease in cardiac mitochondrial biogenesis.493.2 Energy-dependent regulation of PGC-1aactivityIt has been proposed that the phylogenetically conservedAMP-dependent serine/threonine protein kinase (AMPK)plays a role in skeletal muscle-induced mitochondrial biogenesis.PGC-1a is induced by exercise and by chemical activationof AMPK in skeletal muscle (for review see Reznickand Shulman50). Activation of AMPK and mitochondrial biogenesisin muscle in response to chronic energydeprivation is diminished in AMPKa2-kinase-dead mice,revealing the importance of AMPK in this response.51Indeed, cardiac mitochondrial respiration is altered inmice lacking the main catalytic subunit of cardiac and skeletalmuscle AMPK (AMPKa22/2) by a mechanism thatinvolves decreased cardiolipin biosynthesis,52 suggestingthat AMPK is involved in cardiolipin biosynthesis. However,there are no changes in mitochondrial markers or PGC-1aexpression in the hearts of these mice.52,53Sirtuins are highly conserved NAD?-dependent deacetylasesrecently shown to control lifespan. Increased lifespanis associated with augmented mitochondrial oxidative phosphorylationand aerobic capacity. Resveratrol, a polyphenolthat was shown to extend lifespan, increases aerobic capacityin mice and induces expression of genes that encode proteinsinvolved in oxidative phosphorylation and mitochondrialbiogenesis. These effects occur via a SIRT-1-dependentincrease in PGC-1a expression in skeletal muscle andadipose tissue, although not in heart.54 Interestingly, caloricrestriction-induced mitochondrial biogenesis in heart isaccompanied by increased SIRT1 expression in wild-type butnot eNOS2/2 mice.49 These results again indicate that mitochondrialbiogenesis is strictly controlled in the heart.3.3 Hormonal control of PGC-1aThyroid hormones (TH) drastically alter the expression ofnuclear- and mitochondria-encoded genes in severaltissues. TH can control mammalian mitochondrial biogenesisthrough direct and indirect pathways. The direct pathwayinvolves the binding of TH receptors (TRa and b) on TRE recognitionsites on nuclear-encoded mitochondrial genes, andactivation of the mitochondrial genome via a truncated formof TRa called p43.55 However, of the nuclear genes necessaryfor the biogenesis of mitochondria, only a few responddirectly to thyroid hormone.11 An indirect pathway involvesthe control of PGC-1a expression, and activation of itsdownstream transcription cascade.56 However, the effectsof TH on mitochondrial content in the adult heart are notclear. Indeed, one study found that TH treatment of ratsincreased cardiac oxygen consumption, mitochondrial bioenergeticcapacity and expression of markers of mitochondrialbiogenesis such as PGC-1a and its transcriptioncascade.57 In contrast, other studies (including our ownunpublished results) found no change in PGC-1a myocardialexpression/activity with TH treatment.58 Interestingly, aninteraction between PGC-1a and thyroid hormone receptorshas been reported.59 Hypothyroidism induces a decrease inthe maximal oxidative capacity and expression/activity ofmitochondrial enzymes in cardiac muscle, which is independentof PGC-1a and its transcription cascade, suggestingthat there exists a unique mode of regulating mitochondrialrespiration by TH.60 Additionally, thyroid hormones controlcardiolipin biosynthesis and regulate the mitochondrial212 R. Ventura-Clapier et al.Downloaded from https://academic.oup.com/cardiovascres/article-abstract/79/2/208/271402by gueston 07 January 2018protein import machinery, thus providing another ways ofregulating mitochondrial function.9,61,62 [8]Activation of the p38 mitogen-activated protein kinase
(MAPK) pathway in skeletal muscle has been shown topromote PGC-1a expression. However, the cardiac mitochondriaof transgenic mice overexpressing the p38MAPKupstream kinase MAPK-kinase-6 (MKK6) have lower oxidativerespiration and decreased generation of reactive oxygenspecies,46 suggesting that p38MAPK is involved in the negativeregulation of mitochondrial biogenesis.Treatment of various cells with NO donors increases theirmtDNA content, and this is sensitive to removal of NO by NOscavengers.47 The effects of NO occur via increasedexpression of PGC-1a and its down-stream effectors, anddepend on the second messenger cGMP by activation of particulateguanylyl cyclase. Tissues of eNOS2/2 mice such asthe brain, liver, muscle and heart have a slightly decreasedcontent of some mitochondrial proteins.47 However, oxidativecapacity and mitochondrial enzymes are not alteredin hearts of eNOS2/2 mice, suggesting that eNOS is notinvolved in cardiac basal mitochondrial biogenesis.48However, eNOS may be necessary for the cardiac responseto stress, since caloric restriction involves an eNOSdependentincrease in cardiac mitochondrial biogenesis.493.2 Energy-dependent regulation of PGC-1aactivityIt has been proposed that the phylogenetically conservedAMP-dependent serine/threonine protein kinase (AMPK)plays a role in skeletal muscle-induced mitochondrial biogenesis.PGC-1a is induced by exercise and by chemical activationof AMPK in skeletal muscle (for review see Reznickand Shulman50). Activation of AMPK and mitochondrial biogenesisin muscle in response to chronic energydeprivation is diminished in AMPKa2-kinase-dead mice,revealing the importance of AMPK in this response.51Indeed, cardiac mitochondrial respiration is altered inmice lacking the main catalytic subunit of cardiac and skeletalmuscle AMPK (AMPKa22/2) by a mechanism thatinvolves decreased cardiolipin biosynthesis,52 suggestingthat AMPK is involved in cardiolipin biosynthesis. However,there are no changes in mitochondrial markers or PGC-1aexpression in the hearts of these mice.52,53Sirtuins are highly conserved NAD?-dependent deacetylasesrecently shown to control lifespan. Increased lifespanis associated with augmented mitochondrial oxidative phosphorylationand aerobic capacity. Resveratrol, a polyphenolthat was shown to extend lifespan, increases aerobic capacityin mice and induces expression of genes that encode proteinsinvolved in oxidative phosphorylation and mitochondrialbiogenesis. These effects occur via a SIRT-1-dependentincrease in PGC-1a expression in skeletal muscle andadipose tissue, although not in heart.54 Interestingly, caloricrestriction-induced mitochondrial biogenesis in heart isaccompanied by increased SIRT1 expression in wild-type butnot eNOS2/2 mice.49 These results again indicate that mitochondrialbiogenesis is strictly controlled in the heart.3.3 Hormonal control of PGC-1aThyroid hormones (TH) drastically alter the expression ofnuclear- and mitochondria-encoded genes in severaltissues. TH can control mammalian mitochondrial biogenesisthrough direct and indirect pathways. The direct pathwayinvolves the binding of TH receptors (TRa and b) on TRE recognitionsites on nuclear-encoded mitochondrial genes, andactivation of the mitochondrial genome via a truncated formof TRa called p43.55 However, of the nuclear genes necessaryfor the biogenesis of mitochondria, only a few responddirectly to thyroid hormone.11 An indirect pathway involvesthe control of PGC-1a expression, and activation of itsdownstream transcription cascade.56 However, the effectsof TH on mitochondrial content in the adult heart are notclear. Indeed, one study found that TH treatment of ratsincreased cardiac oxygen consumption, mitochondrial bioenergeticcapacity and expression of markers of mitochondrialbiogenesis such as PGC-1a and its transcriptioncascade.57 In contrast, other studies (including our ownunpublished results) found no change in PGC-1a myocardialexpression/activity with TH treatment.58 Interestingly, aninteraction between PGC-1a and thyroid hormone receptorshas been reported.59 Hypothyroidism induces a decrease inthe maximal oxidative capacity and expression/activity ofmitochondrial enzymes in cardiac muscle, which is independentof PGC-1a and its transcription cascade, suggestingthat there exists a unique mode of regulating mitochondrialrespiration by TH.60 Additionally, thyroid hormones controlcardiolipin biosynthesis and regulate the mitochondrial212 R. Ventura-Clapier et al.Downloaded from https://academic.oup.com/cardiovascres/article-abstract/79/2/208/271402by gueston 07 January 2018protein import machinery, thus providing another ways ofregulating mitochondrial function.9,61,62 [8]Mitochondrial transcription factor A (Tfam)
- Nuclear-encoded mitochondrial transcription factor A
- Transcription and replication of mitochondrial DNA
- Binds to a common upstream enhancer of the promoter sites of the two mitochondrial DNA strands
- Cardiac-specific Tfam deletion
- Decreased levels of mtDNA
- Impaired respiratory chain function
- Cardiac hypertrophy
- Progressive cardiomyopathy
- Two proteins that interact with the mammalian mitochondrial RNA polymerase and Tfam
- TFB1M and TFB2M
- Can support promoter-specific mtDNA transcription [8]
Mitochondrial transcription factor A (Tfam)
- Nuclear-encoded mitochondrial transcription factor A
- Transcription and replication of mitochondrial DNA
- Binds to a common upstream enhancer of the promoter sites of the two mitochondrial DNA strands
- Cardiac-specific Tfam deletion
- Decreased levels of mtDNA
- Impaired respiratory chain function
- Cardiac hypertrophy
- Progressive cardiomyopathy
- Two proteins that interact with the mammalian mitochondrial RNA polymerase and Tfam
- TFB1M and TFB2M
- Can support promoter-specific mtDNA transcription [8]
Nuclear respiratory factors 1 and 2
- Linked to the transcriptional control of many mitochondrial genes
- Electrical stimulation of neonatal cardiomyocytes
- Increase in mitochondrial content
- Preceded by enhanced expression of NRF1
- Tfam promoter contains recognition sites for NRF1 and/or NRF2
- Coordination between mitochondrial and nuclear activation [8]
Nuclear respiratory factors 1 and 2
- Linked to the transcriptional control of many mitochondrial genes
- Electrical stimulation of neonatal cardiomyocytes
- Increase in mitochondrial content
- Preceded by enhanced expression of NRF1
- Tfam promoter contains recognition sites for NRF1 and/or NRF2
- Coordination between mitochondrial and nuclear activation [8]
Orphan nuclear receptors ERRa and g
- Target a common set of promoters involved in the
- Uptake of energy substrates
- Production and transport of ATP across the mitochondrial membranes,
- Intracellular fuel sensing
- Ablation of ERRa induces
- Signs of heart failure in mice
- Left ventricular pressure overload
- ERRa is required for the adaptive bioenergetic response
- ERRg deficiency
- Shown to induce complex cardiac defects in embryos
- Changes in the expression of genes involved in mitochondrial biogenesis
- Postnatal transition to oxidative metabolism and fatty acid utilization [8]
Orphan nuclear receptors ERRa and g
- Target a common set of promoters involved in the
- Uptake of energy substrates
- Production and transport of ATP across the mitochondrial membranes,
- Intracellular fuel sensing
- Ablation of ERRa induces
- Signs of heart failure in mice
- Left ventricular pressure overload
- ERRa is required for the adaptive bioenergetic response
- ERRg deficiency
- Shown to induce complex cardiac defects in embryos
- Changes in the expression of genes involved in mitochondrial biogenesis
- Postnatal transition to oxidative metabolism and fatty acid utilization [8]
Peroxisome proliferator-activated receptor gamma co-activator (PGC-1 alpha)
- PGC-1 alpha
- Lacks DNA-binding activity
- Interacts with and co-activates numerous transcription factors
- NRFs on the promoter of mtTFA
- Stimulates Mitochondrial biogenesis and respiration
- Through powerful induction of NRF1 and NRF2 gene expression
- Rich in tissue with high oxidative activity
- Heart
- Brown adipose tissue [8]
- Lesser extent
- Skeletal muscle
- Kidney
- Rapidly induced
- Conditions of increased energy demand such as
- Cold, exercise, and fasting
- PGC-1a to be a master regulator of mitochondrial biogenesis in mammals
- Ectopic expression of PGC-1a in myotubes
- Strongly induces the expression of downstream transcription factors such as
- NRFs
- Tfam
- PGC-1a levels correlate with
- Cardiac and skeletal muscle oxidative capacity
- Major role in setting mitochondrial content
- PGC-1a expression
- Greatly enhanced in the developing mouse heart
- Constitutive cardiospecific PGC-1a overexpression in mice
- Uncontrolled mitochondrial proliferation
- Dilated cardiomyopathy
- Inducible cardiospecific overexpression of PGC-1a
- Dramatic increase in mitochondrial number and size
- Upregulation of genes associated with mitochondrial biogenesis
- In adult
- Modest increase in mitochondrial number
- Perturbation of mitochondrial ultrastructure and development of cardiomyopathy
- Mouse cardiomyocyte (mtch of45% in adult)
- Extremely low cytosolic volume (around 4–7%)
- Any further increase in mitochondrial mass
- At the expense of myofibrillar volume
- Compromising contractile function [8]
- Strict control of mitochondrial volume exists in the adult heart
- In order to keep constant the ratio of mitochondrial to myofibrillar volume
- Clinical signs of heart failure
- Decreased PGC-1a expression
- Only PGC-1a seems to respond to metabolic challenges
- Exercise
- Starvation
- Cold
- Family of three related proteins
- Control major metabolic functions:
- PGC-1-related co-activator (PRC)
- Expressed ubiquitously
- PGC-1a and b
- Enriched in mitochondria-rich tissues
- Cardiac and skeletal muscles [8]
- Additional targets of PGC-1a:
- PGC-1a
- Cooperates with PPARa regulate
- Expression of mitochondrial FAO enzymes
- Transport proteins
- Enabling increases in FAO pathway activity
- Coordinated with mitochondrial biogenesis
- PGC-1? seems to act predominantly upstream of the PPAR receptors
- Co-activator of the PPAR-dependent pathways, rather than being induced by PPARs
- Overexpressed PPARs
- Can indeed bind to a PPAR-responsive element in the promoter of PGC-1 alpha gene
- Increase the reporter gene transcription
- Have never been confirmed in animal models [9]
- Further strategy to activate PGC-1alpha
- Promote its deacetylation via Sirtuin 1 (Sirt1)
Peroxisome proliferator-activated receptor gamma co-activator (PGC-1 alpha)
- PGC-1 alpha
- Lacks DNA-binding activity
- Interacts with and co-activates numerous transcription factors
- NRFs on the promoter of mtTFA
- Stimulates Mitochondrial biogenesis and respiration
- Through powerful induction of NRF1 and NRF2 gene expression
- Rich in tissue with high oxidative activity
- Heart
- Brown adipose tissue [8]
- Lesser extent
- Skeletal muscle
- Kidney
- Rapidly induced
- Conditions of increased energy demand such as
- Cold, exercise, and fasting
- PGC-1a to be a master regulator of mitochondrial biogenesis in mammals
- Ectopic expression of PGC-1a in myotubes
- Strongly induces the expression of downstream transcription factors such as
- NRFs
- Tfam
- PGC-1a levels correlate with
- Cardiac and skeletal muscle oxidative capacity
- Major role in setting mitochondrial content
- PGC-1a expression
- Greatly enhanced in the developing mouse heart
- Constitutive cardiospecific PGC-1a overexpression in mice
- Uncontrolled mitochondrial proliferation
- Dilated cardiomyopathy
- Inducible cardiospecific overexpression of PGC-1a
- Dramatic increase in mitochondrial number and size
- Upregulation of genes associated with mitochondrial biogenesis
- In adult
- Modest increase in mitochondrial number
- Perturbation of mitochondrial ultrastructure and development of cardiomyopathy
- Mouse cardiomyocyte (mtch of45% in adult)
- Extremely low cytosolic volume (around 4–7%)
- Any further increase in mitochondrial mass
- At the expense of myofibrillar volume
- Compromising contractile function [8]
- Strict control of mitochondrial volume exists in the adult heart
- In order to keep constant the ratio of mitochondrial to myofibrillar volume
- Clinical signs of heart failure
- Decreased PGC-1a expression
- Only PGC-1a seems to respond to metabolic challenges
- Exercise
- Starvation
- Cold
- Family of three related proteins
- Control major metabolic functions:
- PGC-1-related co-activator (PRC)
- Expressed ubiquitously
- PGC-1a and b
- Enriched in mitochondria-rich tissues
- Cardiac and skeletal muscles [8]
- Additional targets of PGC-1a:
- PGC-1a
- Cooperates with PPARa regulate
- Expression of mitochondrial FAO enzymes
- Transport proteins
- Enabling increases in FAO pathway activity
- Coordinated with mitochondrial biogenesis
- PGC-1? seems to act predominantly upstream of the PPAR receptors
- Co-activator of the PPAR-dependent pathways, rather than being induced by PPARs
- Overexpressed PPARs
- Can indeed bind to a PPAR-responsive element in the promoter of PGC-1 alpha gene
- Increase the reporter gene transcription
- Have never been confirmed in animal models [9]
- Further strategy to activate PGC-1alpha
- Promote its deacetylation via Sirtuin 1 (Sirt1)
PGC-1b
- Preferentially inducing genes involved in the removal of reactive oxygen species
- Deficiency in PGC-1b in the heart
- General defect in the expression of genes encoding components of the
- Electron transport chain
- Reduced mitochondrial volume fraction
- Blunted response to dobutamine stimulation.
- PGC-1b could play a role in constitutive mitochondrial biogenesis [8]
PGC-1b
- Preferentially inducing genes involved in the removal of reactive oxygen species
- Deficiency in PGC-1b in the heart
- General defect in the expression of genes encoding components of the
- Electron transport chain
- Reduced mitochondrial volume fraction
- Blunted response to dobutamine stimulation.
- PGC-1b could play a role in constitutive mitochondrial biogenesis [8]
PPAR
- Family of transcription factors
- Major role in the expression of proteins involved in extra and intramitochondrial fatty acid transport and oxidation (FAO)
- All PPARs are expressed in the myocardium [8]
- PPARa and b/d
- Main cardiac isoforms [8]
- PPARa binds its
- Obligate partner the retinoid-X-receptor (RXR)
- Resulting heterodimer is involved in the regulation of
- Enzymes
- Transporters
- proteins of FAO [8]
- Activity of the PPAR/RXR complex
- Modulated by the availability of ligands
- Long-chain fatty acids
- And their metabolites [8]
- FAO is increased in cardiomyocytes exposed to
- PPARa
- PPARb/d ligands [8]
- But not PPARg ligands [8]
peroxisome proliferator-activated receptor alpha PPARa
- Regulated
- Fatty acid transport proteins
- Oxidation enzyme genes [8]
- Response to physiological conditions that stimulate FA delivery [8]
peroxisome proliferator-activated receptor alpha PPARa
- Regulated
- Fatty acid transport proteins
- Oxidation enzyme genes [8]
- Response to physiological conditions that stimulate FA delivery [8]
PPARb/d
- Role in the regulation of cardiac lipid metabolism
- Cardiomyocyte-restricted PPARb/d deletion
- Leads to lipotoxic cardiomyopathy [8]
- PPARb/d null mice
- Do not exhibit a fasting-induced phenotype
- Probably serve to regulate basal metabolism [8]
PPARb/d
- Role in the regulation of cardiac lipid metabolism
- Cardiomyocyte-restricted PPARb/d deletion
- Leads to lipotoxic cardiomyopathy [8]
- PPARb/d null mice
- Do not exhibit a fasting-induced phenotype
- Probably serve to regulate basal metabolism [8]
PPARg isoforms
PPARg1
- Predominantly expressed in the heart
Cardiomyocyte-specific PPARg1-KO mice
- Cardiac hypertrophy
- Preserved systolic function
- Signs of heart failure develop with aging
- Abnormal mitochondrial structure
- PPARg could also play a role in mitochondrial biogenesis [8]
PPARg isoforms
PPARg1
- Predominantly expressed in the heart
Cardiomyocyte-specific PPARg1-KO mice
- Cardiac hypertrophy
- Preserved systolic function
- Signs of heart failure develop with aging
- Abnormal mitochondrial structure
- PPARg could also play a role in mitochondrial biogenesis [8]
PPAR
- Family of transcription factors
- Major role in the expression of proteins involved in extra and intramitochondrial fatty acid transport and oxidation (FAO)
- All PPARs are expressed in the myocardium [8]
- PPARa and b/d
- Main cardiac isoforms [8]
- PPARa binds its
- Obligate partner the retinoid-X-receptor (RXR)
- Resulting heterodimer is involved in the regulation of
- Enzymes
- Transporters
- proteins of FAO [8]
- Activity of the PPAR/RXR complex
- Modulated by the availability of ligands
- Long-chain fatty acids
- And their metabolites [8]
- FAO is increased in cardiomyocytes exposed to
- PPARa
- PPARb/d ligands [8]
- But not PPARg ligands [8]
PTP - permeability transition pore
- Transient channel
- Deemed to be formed by ATPase dimers
- Opens upon stress stimuli
- Excessive mitochondrial Ca2 + uptake
- Increased ROS
- Decreased mitochondrial membrane potential
- Low ATP levels [9]
- Opening of the PTP leads to
- Complete dissipation of the mitochondrial membrane potential
- Osmotic swelling of the organelle
- Ultimately mitochondrial disruption
- Release of cytochrome c and other apoptotic triggers
- Cell can eventually die [9]
- Substantial cell loss or damage may lead to organ failure and disease
- Targeting the PTP is a potentially effective strategy to
- Prolong cell survival
- Slow disease progression
- Diminish symptoms severity [9]
- Cyclosporine A (CsA)
- Known to inhibit the PTP
- Through a cyclophilin-D dependent mechanism [9]
- Used in patients with Bethlem/Ullrich congenital muscular dystrophy
- Allelic conditions
- Mutations in the gene encoding collagen VI
- Mitochondrial dysfunction and proneness to apoptosis in skeletal muscle documented in both syndromes
- CsA treatment for one month corrected these phenomena [9]
PTP - permeability transition pore
- Transient channel
- Deemed to be formed by ATPase dimers
- Opens upon stress stimuli
- Excessive mitochondrial Ca2 + uptake
- Increased ROS
- Decreased mitochondrial membrane potential
- Low ATP levels [9]
- Opening of the PTP leads to
- Complete dissipation of the mitochondrial membrane potential
- Osmotic swelling of the organelle
- Ultimately mitochondrial disruption
- Release of cytochrome c and other apoptotic triggers
- Cell can eventually die [9]
- Substantial cell loss or damage may lead to organ failure and disease
- Targeting the PTP is a potentially effective strategy to
- Prolong cell survival
- Slow disease progression
- Diminish symptoms severity [9]
- Cyclosporine A (CsA)
- Known to inhibit the PTP
- Through a cyclophilin-D dependent mechanism [9]
- Used in patients with Bethlem/Ullrich congenital muscular dystrophy
- Allelic conditions
- Mutations in the gene encoding collagen VI
- Mitochondrial dysfunction and proneness to apoptosis in skeletal muscle documented in both syndromes
- CsA treatment for one month corrected these phenomena [9]
Sirt1
- Nuclear deacetylase
- Utilizes the NAD+ moiety to deacetylate acetyl-lysine residues of proteins
- NAD+ exerts a substrate-dependent activation of Sirt1
- Homeostatic significance
- Setting up mitochondrial biogenesis to NAD+ availability [9]
- NAD+ pool can be increased by
- Diet supplementation natural precursor nicotinamide riboside (NR)
- Genetic or pharmacological inhibition of poly(ADP) ribosyl-polymerase 1 (Parp1)
- NAD+ consumer and Sirt1 competitor [9]
- NAD+ higher pool lead to
- Activation of Sirt1 (and other sirtuins)
- Boost mitochondrial respiration
- By inducing OXPHOS genes
- Via the PGC-1? axis [9]
Sirt1
- Nuclear deacetylase
- Utilizes the NAD+ moiety to deacetylate acetyl-lysine residues of proteins
- NAD+ exerts a substrate-dependent activation of Sirt1
- Homeostatic significance
- Setting up mitochondrial biogenesis to NAD+ availability [9]
- NAD+ pool can be increased by
- Diet supplementation natural precursor nicotinamide riboside (NR)
- Genetic or pharmacological inhibition of poly(ADP) ribosyl-polymerase 1 (Parp1)
- NAD+ consumer and Sirt1 competitor [9]
- NAD+ higher pool lead to
- Activation of Sirt1 (and other sirtuins)
- Boost mitochondrial respiration
- By inducing OXPHOS genes
- Via the PGC-1? axis [9]
