The short variant of optic atrophy 1 (OPA1) improves cell survival under oxidative stress.

Optic atrophy 1 (OPA1) is a dynamin protein that mediates mitochondrial fusion at the inner membrane. OPA1 is also necessary for maintaining the cristae and thus essential for supporting cellular energetics. OPA1 exists as membrane-anchored long form (L-OPA1) and short form (S-OPA1) that lacks the transmembrane region and is generated by cleavage of L-OPA1. Mitochondrial dysfunction and cellular stresses activate the inner membrane-associated zinc metallopeptidase OMA1 that cleaves L-OPA1, causing S-OPA1 accumulation. The prevailing notion has been that L-OPA1 is the functional form, whereas S-OPA1 is an inactive cleavage product in mammals, and that stress-induced OPA1 cleavage causes mitochondrial fragmentation and sensitizes cells to death. However, S-OPA1 contains all functional domains of dynamin proteins, suggesting that it has a physiological role. Indeed, we recently demonstrated that S-OPA1 can maintain cristae and energetics through its GTPase activity, despite lacking fusion activity. Here, applying oxidant insult that induces OPA1 cleavage, we show that cells unable to generate S-OPA1 are more sensitive to this stress under obligatory respiratory conditions, leading to necrotic death. These findings indicate that L-OPA1 and S-OPA1 differ in maintaining mitochondrial function. Mechanistically, we found that cells that exclusively express L-OPA1 generate more superoxide and are more sensitive to Ca2+-induced mitochondrial permeability transition, suggesting that S-OPA1, and not L-OPA1, protects against cellular stress. Importantly, silencing of OMA1 expression increased oxidant-induced cell death, indicating that stress-induced OPA1 cleavage supports cell survival. Our findings suggest that S-OPA1 generation by OPA1 cleavage is a survival mechanism in stressed cells

p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction

RATIONALE: Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent up-regulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown. OBJECTIVE: We previously demonstrated increased p90RSK activation in the diabetic heart. As a logical extension of this work, we now investigate whether p90RSK activation inhibits ERK5-mediated CHIP activation, and subsequently increases ICER levels and apoptosis. METHODS AND RESULTS: p90RSK activation inhibits ERK5/CHIP association and CHIP Ub ligase activity. p90RSK and CHIP share a common binding site in the ERK5 C-terminal domain (aa571-807). Overexpression of either p90RSK or an ERK5 fragment (aa571-807) inhibits ERK5/CHIP association, suggesting that p90RSK and CHIP competes for ERK5 binding and that p90RSK activation is critical for inhibiting ERK5/CHIP interaction. We also identified ERK5-S496 as being directly phosphorylated by p90RSK, and demonstrated that an ERK5-S496A mutant significantly impairs Angiotensin II-mediated inhibition of CHIP activity and subsequent increase in ICER levels. In vivo, either cardiac specific depletion of ERK5 or overexpression of p90RSK inhibits CHIP activity and accelerates cardiac apoptosis after MI--a phenomenon fully reversible by activating ERK5. CONCLUSION: These data suggest a role for p90RSK in inhibiting CHIP activity and promoting cardiac apoptosis through binding to and phosphorylation of ERK5-S496

p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction

Cardiomyocyte apoptosis is one of the key events in the development and progression of heart failure, and a crucial role for ICER (inducible cAMP early repressor) in this process has been previously reported. ERK5 is known to inhibit cardiac apoptosis after myocardial infarction (MI), especially in hyperglycemic states, via association with CHIP ubiquitin (Ub) ligase and subsequent up-regulation of CHIP ligase activity, which induces ICER ubiquitination and subsequent protein degradation. The regulatory mechanism governing ERK5/CHIP interaction is unknown

Mitochondrial Membrane Dynamics—Functional Positioning of OPA1

The maintenance of mitochondrial energetics requires the proper regulation of mitochondrial morphology, and vice versa. Mitochondrial dynamins control mitochondrial morphology by mediating fission and fusion. One of them, optic atrophy 1 (OPA1), is the mitochondrial inner membrane remodeling protein. OPA1 has a dual role in maintaining mitochondrial morphology and energetics through mediating inner membrane fusion and maintaining the cristae structure. OPA1 is expressed in multiple variant forms through alternative splicing and post-translational proteolytic cleavage, but the functional differences between these variants have not been completely understood. Recent studies generated new information regarding the role of OPA1 cleavage. In this review, we will first provide a brief overview of mitochondrial membrane dynamics by describing fission and fusion that are mediated by mitochondrial dynamins. The second part describes OPA1-mediated fusion and energetic maintenance, the role of OPA1 cleavage, and a new development in OPA1 function, in which we will provide new insight for what OPA1 does and what proteolytic cleavage of OPA1 is for

Automated Source Code Instrumentation for Verifying Potential Vulnerabilities

Part 6: Software VulnerabilitiesInternational audienceWith a rapid yearly growth rate, software vulnerabilities are making great threats to the system safety. In theory, detecting and removing vulnerabilities before the code gets ever deployed can greatly ensure the quality of software released. However, due to the enormous amount of code being developed as well as the lack of human resource and expertise, severe vulnerabilities still remain concealed or cannot be revealed effectively. Current source code auditing tools for vulnerability discovery either generate too many false positives or require overwhelming manual efforts to report actual software flaws. In this paper, we propose an automatic verification mechanism to discover and verify vulnerabilities by using program source instrumentation and concolic testing. In the beginning, we leverage CIL to statically analyze the source code including extracting the program CFG, locating the security sinks and backward tracing the sensitive variables. Subsequently, we perform automated program instrumentation to insert security probes ready for the vulnerability verification. Finally, the instrumented program source is passed to the concolic testing engine to verify and report the existence of an actual vulnerability. We demonstrate the efficacy and efficiency of our mechanism by implementing a prototype system and perform experiments with nearly 4000 test cases from Juliet Test Suite. The results show that our system can verify over 90 % of test cases and it reports buffer overflow flaws with P r e c i s i o n = 100 % (0 FP) and R e c a l l = 94.91 %. In order to prove the practicability of our system working in real world programs, we also apply our system on 2 popular Linux utilities, Bash and Cpio. As a result, our system finds and verifies vulnerabilities in a fully automatic way with no false positives