Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

Binding and allosteric transmission of histone H3 Lys-4 trimethylation to the recombinase RAG-1 are separable functions of the RAG-2 plant homeodomain finger

V(D)J recombination is initiated by the recombination-activating gene protein (RAG) recombinase, consisting of RAG-1 and RAG-2 subunits. The susceptibility of gene segments to cleavage by RAG is associated with gene transcription and with epigenetic marks characteristic of active chromatin, including histone H3 trimethylated at lysine 4 (H3K4me3). Binding of H3K4me3 by a plant homeodomain (PHD) in RAG-2 induces conformational changes in RAG-1, allosterically stimulating substrate binding and catalysis. To better understand the path of allostery from the RAG-2 PHD finger to RAG-1, here we employed phylogenetic substitution. We observed that a chimeric RAG-2 protein in which the mouse PHD finger is replaced by the corresponding domain from the shark Chiloscyllium punctatum binds H3K4me3 but fails to transmit an allosteric signal, indicating that binding of H3K4me3 by RAG-2 is insufficient to support recombination. By substituting residues in the C. punctatum PHD with the corresponding residues in the mouse PHD and testing for rescue of allostery, we demonstrate that H3K4me3 binding and transmission of an allosteric signal to RAG-1 are separable functions of the RAG-2 PHD finger.

Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D in Drosophila neurons

A healthy population of mitochondria, maintained by proper fission, fusion, and degradation, is critical for the long-term survival and function of neurons. Here, our discovery of mitophagy intermediates in fission-impaired Drosophila neurons brings new perspective into the relationship between mitochondrial fission and mitophagy. Neurons lacking either the ataxia disease gene Vps13D or the dynamin related protein Drp1 contain enlarged mitochondria that are engaged with autophagy machinery and also lack matrix components due to rupture. Reporter assays combined with genetic studies imply that mitophagy both initiates and is completed in Drp1 impaired neurons, but fails to complete in Vps13D impaired neurons, which accumulate compromised mitochondria within stalled mito-phagophores. Our findings imply that in fission-defective neurons, mitophagy becomes induced, and that the lipid channel containing protein Vps13D has separable functions in mitochondrial fission and phagophore elongation.

State evolution for approximate message passing with non-separable functions

Given a high-dimensional data matrix $\boldsymbol{A}\in{{\mathbb{R}}}^{m\times n}$, approximate message passing (AMP) algorithms construct sequences of vectors $\boldsymbol{u}^{t}\in{{\mathbb{R}}}^{n}$, ${\boldsymbol v}^{t}\in{{\mathbb{R}}}^{m}$, indexed by $t\in \{0,1,2\dots \}$ by iteratively applying $\boldsymbol{A}$ or $\boldsymbol{A}^{{\textsf T}}$ and suitable nonlinear functions, which depend on the specific application. Special instances of this approach have been developed—among other applications—for compressed sensing reconstruction, robust regression, Bayesian estimation, low-rank matrix recovery, phase retrieval and community detection in graphs. For certain classes of random matrices $\boldsymbol{A}$, AMP admits an asymptotically exact description in the high-dimensional limit $m,n\to \infty $, which goes under the name of state evolution. Earlier work established state evolution for separable nonlinearities (under certain regularity conditions). Nevertheless, empirical work demonstrated several important applications that require non-separable functions. In this paper we generalize state evolution to Lipschitz continuous non-separable nonlinearities, for Gaussian matrices $\boldsymbol{A}$. Our proof makes use of Bolthausen’s conditioning technique along with several approximation arguments. In particular, we introduce a modified algorithm (called LoAMP for Long AMP), which is of independent interest.