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Mitochondrial fragmentation and bioenergetic failure manifest in Huntington’s disease (HD), a fatal neurodegenerative disease. The factors that couple mitochondrial fusion/fission with bioenergetics and their impacts on neurodegeneration however remain poorly understood. Our proteomic analysis identifies mitochondrial protein ATAD3A as an interactor of mitochondrial fission GTPase, Drp1, in HD. Here we show that, in HD, ATAD3A dimerization due to deacetylation at K135 residue is required for Drp1-mediated mitochondrial fragmentation. Disturbance of ATAD3A steady state impairs mtDNA maintenance by disrupting TFAM/mtDNA binding. Blocking Drp1/ATAD3A interaction with a peptide, DA1, abolishes ATAD3A oligomerization, suppresses mitochondrial fragmentation and mtDNA lesion, and reduces bioenergetic deficits and cell death in HD mouse- and patient-derived cells. DA1 treatment reduces behavioral and neuropathological phenotypes in HD transgenic mice. Our findings demonstrate that ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance, suggesting that DA1 might be useful for developing HD therapeutics. Huntington’s disease leads to mitochondrial fragmentation and bioenergetic failure, although how the two events are connected is poorly understood. Here, Zhao et al. identify ATAD3A as a molecular linker and show that a peptide inhibitor of ATAD3A oligomerization suppresses HD phenotypes.

A high gain nonisolated DC-DC converter using a single power semiconductor switch is proposed in this article. The operation of the proposed converter is explained under continuous conduction mode (CCM), discontinuous conduction mode (DCM), and boundary conduction mode (BCM). The mathematical expressions for steady-state voltage gain, voltage stress, and current stress of diodes and switch are provided. Also, the design of inductors and capacitors in the CCM mode is explained with appropriate mathematical equations. The proposed topology is tested with a 200 W prototype at 50 kHz and a 60% duty cycle. The dynamic behavior of the proposed converter is examined by changing the duty cycle value and also load values. The proposed converter is verified with experimental results to prove the effectiveness of its operation. The proposed converter provides higher steady-state voltage gain as compared with recently developed topologies. The efficiency and power density of the proposed converter is 90% and 1.16 kW/L, respectively.

Key to successful retina regeneration in zebrafish are Müller glia (MG) that respond to retinal injury by dedifferentiating into a cycling population of retinal progenitors. Although recent studies have identified several genes involved in retina regeneration, the signaling mechanisms underlying injury-dependent MG proliferation have remained elusive. Here we report that canonical Wnt signaling controls the proliferation of MG-derived retinal progenitors. We found that injury-dependent induction of Ascl1a suppressed expression of the Wnt signaling inhibitor, Dkk, and induced expression of the Wnt ligand, Wnt4a. Genetic and pharmacological inhibition of Wnt signaling suppressed injury-dependent proliferation of MG-derived progenitors. Remarkably, in the uninjured retina, glycogen synthase kinase-3β (GSK-3β) inhibition was sufficient to stimulate MG dedifferentiation and the formation of multipotent retinal progenitors that were capable of differentiating into all major retinal cell types. Importantly, Ascl1a expression was found to contribute to the multipotential character of these progenitors. Our data suggest that Wnt signaling and GSK-3β inhibition, in particular, are crucial for successful retina regeneration.

Green fluorescent protein (GFP)-tagging is the prevalent strategy to monitor protein dynamics in living cells. However, the consequences of appending the bulky GFP moiety to the protein of interest are rarely investigated. Here, using a powerful combination of quantitative fluorescence spectroscopic and imaging techniques, we have examined the oligomerization dynamics of the GFP-tagged mitochondrial fission GTPase dynamin-related protein 1 (Drp1) both in vitro and in vivo. We find that GFP-tagged Drp1 exhibits impaired oligomerization equilibria in solution that corresponds to a greatly diminished cooperative GTPase activity in comparison to native Drp1 . Consequently, GFP-tagged Drp1 constitutes aberrantly stable, GTP-resistant supramolecular assemblies both in vitro and in vivo, neither of which reflects a more dynamic native Drp1 oligomerization state. Indeed, GFP-tagged Drp1 is detected more frequently per unit length over mitochondria in Drp1-null mouse embryonic fibroblasts (MEFs) compared to wild-type ( wt ) MEFs, indicating that the drastically reduced GTP turnover restricts oligomer disassembly from the mitochondrial surface relative to mixed oligomers comprising native and GFP-tagged Drp1. Yet, GFP-tagged Drp1 retains the capacity to mediate membrane constriction in vitro and mitochondrial division in vivo. These findings suggest that instead of robust assembly-disassembly dynamics, persistent Drp1 higher-order oligomerization over membranes is sufficient for mitochondrial fission.

Sorting nexins (SNX) are a family of PX domain-containing proteins with pivotal roles in trafficking and signaling. SNX-BARs, which also have a curvature-generating Bin/Amphiphysin/Rvs (BAR) domain, have membrane-remodeling functions, particularly at the endosome. The minimal PX-BAR module is a dimer mediated by BAR-BAR interactions. Many SNX-BAR proteins, however, additionally have low-complexity N-terminal regions of unknown function. Here, we present the cryo-EM structure of the full-length SNX-BAR Mvp1, which is an autoinhibited tetramer. The tetramer is a dimer of dimers, wherein the membrane-interacting BAR surfaces are sequestered and the PX lipid-binding sites are occluded. The N-terminal low-complexity region of Mvp1 is essential for tetramerization. Mvp1 lacking its N-terminus is dimeric and exhibits enhanced membrane association. Membrane binding and remodeling by Mvp1 therefore requires unmasking of the PX and BAR domain lipid-interacting surfaces. This work reveals a tetrameric configuration of a SNX-BAR protein that provides critical insight into SNX-BAR function and regulation. SNX-BAR proteins are a family of PX and BAR domain-containing proteins with pivotal roles in trafficking processes. Here authors present the cryo-EM structure of the full-length fungal SNX-BAR Mvp1, which is an autoinhibited tetramer and provides critical insight into SNX-BAR function and regulation.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery. Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.

The paper delves into the complexities of Mobile Ad hoc Networks (MANETs), which consist of a diverse array of wireless nodes. In such networks, routing packets poses a significant challenge due to their dynamic nature. Despite the variety of techniques available for optimizing routing in MANETs, persistent issues like packet loss, routing overhead, and End-to-End Delay (EED) remain prevalent. In response to these challenges, the paper proposes a novel approach for efficient Data Communication (DC) by introducing a Link Stability (LS)-based optimal routing path. This approach leverages several advanced techniques, including Pearson Correlation Coefficient SWIFFT (PCC-SWIFFT), Galois-based Digital Signature Algorithm (G-DSA), and Entropy-based Gannet Optimization Algorithm (E-GOA). The proposed methodology involves a systematic process. Initially, the nodes in the MANET are initialized to establish the network infrastructure. Subsequently, the Canberra-based K Means (C-K Means) algorithm is employed to identify Neighboring Nodes (NNs), which are pivotal for creating communication links within the network. To ensure secure communication, secret keys (SK) are generated for both the Sender Node (SN) and the Receiver Node (RN) using Galois Theory. Following this, PCC-SWIFFT methodologies are utilized to generate hash codes, serving as unique identifiers for data packets or routing information. Signatures are created and verified at the SN and RN using the G-DSA. Verified nodes are subsequently added to the routing entry table, facilitating the establishment of multiple paths within the network. The Optimal Path (OP) is selected using the E-GOA, considering factors such as link stability and network congestion. Finally, Data Communication (DC) is initiated, continuously monitoring LS to ensure optimal routing performance. Comparative analysis with existing methodologies demonstrates the superior performance of the proposed model. In summary, the proposed approach offers a comprehensive solution to enhance routing efficiency in MANETs by addressing critical issues and leveraging advanced algorithms for key generation, signature verification, and path optimization

The Canadian League Against Epilepsy initiated a virtual epilepsy education program, conducting 29 webinars from March 2021 to September 2023. We report our experience, with the goal to inspire other groups to develop inclusive, equitable, and free educational spaces with a worldwide reach. Monthly sessions drew a median attendance of 118 participants, predominantly Canadian but also international, including physicians (58.9%) and trainees (22.8%). Post-webinar surveys (average 40% response rate) noted high satisfaction, a strong inclination to recommend the sessions, and an interest in clinical case-based topics. We plan to consider integrating a self-assessment section evaluating knowledge gained after each seminar.

In zebrafish, retinal injury stimulates Müller glia (MG) reprograming, allowing them to generate multipotent progenitors that replace damaged cells and restore vision. Recent studies suggest that transcriptional repression may underlie these events. To identify transcriptional repressors, we compared the transcriptomes of MG and MG-derived progenitors and identified insm1a , a repressor exhibiting a biphasic pattern of expression that is essential for retina regeneration. Insm1a was found to suppress ascl1a and its own expression, and link injury-dependent ascl1a induction with the suppression of the Wnt inhibitor dickkopf ( dkk ), which is necessary for MG dedifferentiation. We also found that Insm1a was responsible for sculpting the zone of injury-responsive MG by suppressing h b - e g f a expression. Finally, we provide evidence that Insm1a stimulates progenitor cell-cycle exit by suppressing a genetic program driving progenitor proliferation. Our studies identify Insm1a as a key regulator of retina regeneration and provide a mechanistic understanding of how it contributes to multiple phases of this process. Goldman and colleagues report that the transcriptional repressor Insm1a is essential for retinal regeneration following injury in fish. Insm1a suppresses the expression of Ascl1a to promote Müller glial cells’ dedifferentiation at early stages of regeneration, and defines the regeneration zone by negatively regulating the expression of the heparin-binding EGF. It also halts the proliferation of retinal progenitors in the late stages of the process.

Mitochondria form tubular networks that undergo coordinated cycles of fission and fusion. Emerging evidence suggests that a direct yet unresolved interaction of the mechanoenzymatic GTPase dynamin-related protein 1 (Drp1) with mitochondrial outer membrane–localized cardiolipin (CL), externalized under stress conditions including mitophagy, catalyzes essential mitochondrial hyperfragmentation. Here, using a comprehensive set of structural, biophysical, and cell biological tools, we have uncovered a CL-binding motif (CBM) conserved between the Drp1 variable domain (VD) and the unrelated ADP/ATP carrier (AAC/ANT) that intercalates into the membrane core to effect specific CL interactions. CBM mutations that weaken VD–CL interactions manifestly impair Drp1-dependent fission under stress conditions and induce “donut” mitochondria formation. Importantly, VD membrane insertion and GTP-dependent conformational rearrangements mediate only transient CL nonbilayer topological forays and high local membrane constriction, indicating that Drp1–CL interactions alone are insufficient for fission. Our studies establish the structural and mechanistic bases of Drp1–CL interactions in stressinduced mitochondrial fission.