- Email: [email protected]
The mitochondrial metabolic checkpoint, stem cell aging and rejuvenation
S18
M. Casal / Free Radical Biology and Medicine 120 (2018) S6–S23
L-46
L-48
The mitochondrial metabolic checkpoint, stem cell aging and rejuvenation
Mitochondria in kidney disease and recovery Rick G. Schnellmann
Danica Chen University of Arizona College of Medicine, Tucson, AZ, USA University of California Berkeley, CA, USA
Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced and mitochondrial stress is increased. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. These processes are critically regulated by several sirtuin family members. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions.
The kidney requires oxidative phosphorylation for ATP production and the many renal functions. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy. We proposed that pharmacological stimulation of mitochondrial biogenesis (MB) could restore mitochondrial and renal function. Agonists of the beta 2-adrergic receptor and the 5-HT1F receptor stimulated MB in mice through the Akt/eNOS/cGMP/PKG/ PGC -1alpha pathway. PGC-1alpha is the "master regulator" of MB. Treatment of AKI and diabetic nephropathy mice, after renal dysfunction occurred, with agonists to these receptors stimulated MB and mitochondrial function and promoted recovery of renal function. In addition, this approach was also effective in mice models of spinal cord injury, restoring mitochondrial function and locomotion. These results reveal novel mechanisms of MB provide the foundation for new chemicals that induce MB to treat acute and chronic organ injuries.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.077
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.075
L-49
Bright and dark sides of KEAP1-NRF2 system in carcinogenesis L-47
Keeping mitochondria in shape: A matter of life and death
Hozumi Motohashi 1, Tomoaki Ida 2, Md. Morshedul Alam 1, Hiroshi Kitamura 1, Takaaki Akaike 2 1 2
Luca Scorrano Veneto Institute of Molecular Medicine, Dept. of Biology, University of Padua, Italy
Mitochondrial morphology changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Today we will discuss our recent in vitro and in vivo results that place the inner mitochondrial membrane shaping protein Optic atrophy 1 (OPA1) at the crossroad between oxidative tissue damage, intermediate metabolism and angiogenesis, the physiological process through which new blood vessels form from pre-existing ones.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.076
IDAC, Tohoku University, Sendai, Japan Tohoku University Graduate School of Medicine, Sendai, Japan
KEAP1-NRF2 system is a sulfur-employing defense mechanism. NRF2mediated activation of the cytoprotective genes substantially mediates chemoprevention of cancers. Recent studies described that NRF2 activation in tumor microenvironment is also beneficial resulting in the potentiation of anticancer immunity. In contrast to these bright sides of NRF2 function, cancer cells often hijack the KEAP1-NRF2 system, taking growth and survival advantages brought by NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients. NRF2 enhances survival of cancers by activating cytoprotective genes and promotes tumorigenesis by modulating cellular metabolism. Recently we have found that excretion of sulfur-containing metabolites is positively correlated with NRF2 activity of cancer cells. Detailed analysis of sulfur-containing metabolites has revealed that NRF2 promotes sulfur redox metabolism, which is likely to be coupled with mitochondrial bioenergetic activity. Because antioxidant and detoxification functions of NRF2 heavily rely on ATP-consuming reactions, such as glutathione synthesis, it would be reasonable for NRF2 to facilitate mitochondrial activity for efficient energy production.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.078
M. Casal / Free Radical Biology and Medicine 120 (2018) S6–S23
L-46
L-48
The mitochondrial metabolic checkpoint, stem cell aging and rejuvenation
Mitochondria in kidney disease and recovery Rick G. Schnellmann
Danica Chen University of Arizona College of Medicine, Tucson, AZ, USA University of California Berkeley, CA, USA
Cell cycle checkpoints are surveillance mechanisms in eukaryotic cells that monitor the condition of the cell, repair cellular damages, and allow the cell to progress through the various phases of the cell cycle when conditions become favorable. Recent advances in hematopoietic stem cell (HSC) biology highlight a mitochondrial metabolic checkpoint that is essential for HSCs to return to the quiescent state. As quiescent HSCs enter the cell cycle, mitochondrial biogenesis is induced and mitochondrial stress is increased. Mitochondrial unfolded protein response and mitochondrial oxidative stress response are activated to alleviate stresses and allow HSCs to exit the cell cycle and return to quiescence. These processes are critically regulated by several sirtuin family members. Because loss of HSC quiescence results in the depletion of the HSC pool and compromised tissue regeneration, deciphering the molecular mechanisms that regulate the mitochondrial metabolic checkpoint in HSCs will increase our understanding of hematopoiesis and how it becomes dysregulated under pathological conditions and during aging. More broadly, this knowledge is instrumental for understanding the maintenance of cells that convert between quiescence and proliferation to support their physiological functions.
The kidney requires oxidative phosphorylation for ATP production and the many renal functions. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy. We proposed that pharmacological stimulation of mitochondrial biogenesis (MB) could restore mitochondrial and renal function. Agonists of the beta 2-adrergic receptor and the 5-HT1F receptor stimulated MB in mice through the Akt/eNOS/cGMP/PKG/ PGC -1alpha pathway. PGC-1alpha is the "master regulator" of MB. Treatment of AKI and diabetic nephropathy mice, after renal dysfunction occurred, with agonists to these receptors stimulated MB and mitochondrial function and promoted recovery of renal function. In addition, this approach was also effective in mice models of spinal cord injury, restoring mitochondrial function and locomotion. These results reveal novel mechanisms of MB provide the foundation for new chemicals that induce MB to treat acute and chronic organ injuries.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.077
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.075
L-49
Bright and dark sides of KEAP1-NRF2 system in carcinogenesis L-47
Keeping mitochondria in shape: A matter of life and death
Hozumi Motohashi 1, Tomoaki Ida 2, Md. Morshedul Alam 1, Hiroshi Kitamura 1, Takaaki Akaike 2 1 2
Luca Scorrano Veneto Institute of Molecular Medicine, Dept. of Biology, University of Padua, Italy
Mitochondrial morphology changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Today we will discuss our recent in vitro and in vivo results that place the inner mitochondrial membrane shaping protein Optic atrophy 1 (OPA1) at the crossroad between oxidative tissue damage, intermediate metabolism and angiogenesis, the physiological process through which new blood vessels form from pre-existing ones.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.076
IDAC, Tohoku University, Sendai, Japan Tohoku University Graduate School of Medicine, Sendai, Japan
KEAP1-NRF2 system is a sulfur-employing defense mechanism. NRF2mediated activation of the cytoprotective genes substantially mediates chemoprevention of cancers. Recent studies described that NRF2 activation in tumor microenvironment is also beneficial resulting in the potentiation of anticancer immunity. In contrast to these bright sides of NRF2 function, cancer cells often hijack the KEAP1-NRF2 system, taking growth and survival advantages brought by NRF2. Increased accumulation of NRF2 in cancers is strongly associated with the poor prognoses of cancer patients. NRF2 enhances survival of cancers by activating cytoprotective genes and promotes tumorigenesis by modulating cellular metabolism. Recently we have found that excretion of sulfur-containing metabolites is positively correlated with NRF2 activity of cancer cells. Detailed analysis of sulfur-containing metabolites has revealed that NRF2 promotes sulfur redox metabolism, which is likely to be coupled with mitochondrial bioenergetic activity. Because antioxidant and detoxification functions of NRF2 heavily rely on ATP-consuming reactions, such as glutathione synthesis, it would be reasonable for NRF2 to facilitate mitochondrial activity for efficient energy production.
E-mail address: [email protected]
http://dx.doi.org/10.1016/j.freeradbiomed.2018.04.078