- Email: [email protected]
Modulation of Parkin-dependent mitophagy and mitochondrial health
Free Radical Biology and Medicine 108 (2017) S4–S13
Contents lists available at ScienceDirect
Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed
OCC/SFRRE 2017 Oral Presentations Abstracts
OP-01
OP-03
Treatment of sarcopenia by targeting Akt and muscle specific ubiquitin ligases. Evidence from mice and from a clinical trial
Modulation of Parkin-dependent mitophagy and mitochondrial health Antonio Zorzano
Jose Viña Department of Physiology, University of Valencia, Spain Disuse muscle wasting may take place as a result of several such as joint immobilization, inactivity or bed rest. There are no good therapies to treat it. Allopurinol, a drug commonly used to treat hyperuricemia and gout, protects muscle damage, specially after exhaustive exercise and results in functional gains in old persons. Thus, we tested its effect in the prevention of atrophy of the soleus muscle after two weeks of hindlimb unloading in experimental animals (mice), and lower leg immobilization following ankle sprain in humans (Registration of the clinical Trial: EUDRACT2011-003541-17). We have found show that allopurinol protects against muscle atrophy in both mice and humans. The protective effect of allopurinol is similar, or even superior, to that of resistance exercise which is the bestknown way to prevent muscle mass loss in disuse human models. We have also found that allopurinol protects against muscle mass loss by inhibiting the expression of ubiquitin ligases. Thus, the ubiquitin-proteasome pathway is an adequate therapeutic target to inhibit muscle wasting and underpins the role of allopurinol as a non-hormonal intervention to treat disuse muscle atrophy. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.040
Institute for Research in Biomedicine (IRB) Barcelona, University of Barcelona, and CIBERDEM, Spain A correct mitochondrial function requires a balance between the processes of mitochondrial biogenesis, mitochondrial dynamics and mitophagy. Mitophagy represents the only known cellular mechanism that can actually mediate the degradation of entire organelles. During mitophagy, autophagy receptors localized at the outer mitochondrial membrane initiate the attachment of autophagosomes to the mitochondria via their LIR motif. One group of mitophagy receptors contains a ubiquitin-binding domain which localizes them to Parkin-ubiquitylated mitochondria, which includes p62, NBR1, optineurin, and NDP52. Parkin encodes an E3 ubiquitin ligase, a substrate recognition member of the ubiquitination pathway. Damaged mitochondria accumulate a PINK1 at the mitochondrial outer membrane, which recruits Parkin, and in turn, it mediates the ubiquitination of protein targets such as Mitofusin 2. Ubiquitinated proteins and PINK1-dependent phosphorylation of adapter proteins trigger the binding of lipidated LC3, and initiates mitochondrial degradation. There is some evidence for the existence of modulators of the Parkin-PINK1 pathway such as the deubiquitinating enzymes USP8, and USP30. Here we will document another factor that while activating general macroautophagy, prevents PINK1/Parkin-dependent mitophagy in mammalian cells. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.042
OP-02
Reactive oxygen species in tissue repair and its disorders Karin Scharffetter-Kochanek Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany No abstract was supplied by the speaker.
OP-04
Redox Signals in Healthspan and Metabolic Disease Michael Ristow Energy Metabolism Laboratory, ETH Zürich (Swiss Federal Institute of Technology Zurich), Schwerzenbach, CH-8603, Switzerland
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.041 Processing and intermediate metabolism of macronutrients are essential components of any life. Facultative or obligatory conversion of carbohydrates as well as fatty and amino acids into readily available http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.040 0891-5849/
Contents lists available at ScienceDirect
Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed
OCC/SFRRE 2017 Oral Presentations Abstracts
OP-01
OP-03
Treatment of sarcopenia by targeting Akt and muscle specific ubiquitin ligases. Evidence from mice and from a clinical trial
Modulation of Parkin-dependent mitophagy and mitochondrial health Antonio Zorzano
Jose Viña Department of Physiology, University of Valencia, Spain Disuse muscle wasting may take place as a result of several such as joint immobilization, inactivity or bed rest. There are no good therapies to treat it. Allopurinol, a drug commonly used to treat hyperuricemia and gout, protects muscle damage, specially after exhaustive exercise and results in functional gains in old persons. Thus, we tested its effect in the prevention of atrophy of the soleus muscle after two weeks of hindlimb unloading in experimental animals (mice), and lower leg immobilization following ankle sprain in humans (Registration of the clinical Trial: EUDRACT2011-003541-17). We have found show that allopurinol protects against muscle atrophy in both mice and humans. The protective effect of allopurinol is similar, or even superior, to that of resistance exercise which is the bestknown way to prevent muscle mass loss in disuse human models. We have also found that allopurinol protects against muscle mass loss by inhibiting the expression of ubiquitin ligases. Thus, the ubiquitin-proteasome pathway is an adequate therapeutic target to inhibit muscle wasting and underpins the role of allopurinol as a non-hormonal intervention to treat disuse muscle atrophy. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.040
Institute for Research in Biomedicine (IRB) Barcelona, University of Barcelona, and CIBERDEM, Spain A correct mitochondrial function requires a balance between the processes of mitochondrial biogenesis, mitochondrial dynamics and mitophagy. Mitophagy represents the only known cellular mechanism that can actually mediate the degradation of entire organelles. During mitophagy, autophagy receptors localized at the outer mitochondrial membrane initiate the attachment of autophagosomes to the mitochondria via their LIR motif. One group of mitophagy receptors contains a ubiquitin-binding domain which localizes them to Parkin-ubiquitylated mitochondria, which includes p62, NBR1, optineurin, and NDP52. Parkin encodes an E3 ubiquitin ligase, a substrate recognition member of the ubiquitination pathway. Damaged mitochondria accumulate a PINK1 at the mitochondrial outer membrane, which recruits Parkin, and in turn, it mediates the ubiquitination of protein targets such as Mitofusin 2. Ubiquitinated proteins and PINK1-dependent phosphorylation of adapter proteins trigger the binding of lipidated LC3, and initiates mitochondrial degradation. There is some evidence for the existence of modulators of the Parkin-PINK1 pathway such as the deubiquitinating enzymes USP8, and USP30. Here we will document another factor that while activating general macroautophagy, prevents PINK1/Parkin-dependent mitophagy in mammalian cells. E-mail address: [email protected] http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.042
OP-02
Reactive oxygen species in tissue repair and its disorders Karin Scharffetter-Kochanek Department of Dermatology and Allergic Diseases, University of Ulm, Ulm, Germany No abstract was supplied by the speaker.
OP-04
Redox Signals in Healthspan and Metabolic Disease Michael Ristow Energy Metabolism Laboratory, ETH Zürich (Swiss Federal Institute of Technology Zurich), Schwerzenbach, CH-8603, Switzerland
http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.041 Processing and intermediate metabolism of macronutrients are essential components of any life. Facultative or obligatory conversion of carbohydrates as well as fatty and amino acids into readily available http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.040 0891-5849/