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Autophagy is a conserved process that catabolizes intracellular components to maintain energy homeostasis and to protect cells against stress. Autophagy has crucial roles during development and disease, and evidence accumulated over the past decade indicates that autophagy also has a direct role in modulating ageing. In particular, elegant studies using yeasts, worms, flies and mice have demonstrated a broad requirement for autophagy-related genes in the lifespan extension observed in a number of conserved longevity paradigms. Moreover, several new and interesting concepts relevant to autophagy and its role in modulating longevity have emerged. First, select tissues may require or benefit from autophagy activation in longevity paradigms, as tissue-specific overexpression of single autophagy genes is sufficient to extend lifespan. Second, selective types of autophagy may be crucial for longevity by specifically targeting dysfunctional cellular components and preventing their accumulation. And third, autophagy can influence organismal health and ageing even non-cell autonomously, and thus, autophagy stimulation in select tissues can have beneficial, systemic effects on lifespan. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy.

N6-methyldeoxyadenine (6mA), a major type of DNA methylation in bacteria, represents a part of restriction-modification systems to discriminate host genome from invader DNA 1 . With the recent advent of more sensitive detection techniques, 6mA has also been detected in some eukaryotes 2 – 8 . However, the physiological function of this epigenetic mark in eukaryotes remains elusive. Heritable changes in DNA 5mC methylation have been associated with transgenerational inheritance of responses to a high-fat diet 9 , thus raising the exciting possibility that 6mA may also be transmitted across generations and serve as a carrier of inheritable information. Using Caenorhabditis elegans as a model, here we report that histone H3K4me3 and DNA 6mA modifications are required for the transmission of mitochondrial stress adaptations to progeny. Intriguingly, the global DNA 6mA level is significantly elevated following mitochondrial perturbation. N6-methyldeoxyadenine marks mitochondrial stress response genes and promotes their transcription to alleviate mitochondrial stress in progeny. These findings suggest that 6mA is a precisely regulated epigenetic mark that modulates stress response and signals transgenerational inheritance in C. elegans . Ma et al. show that exposure of Caenorhabditis elegans to mitochondrial stress triggers stress adaptation in offspring, which is mediated by 6mA DNA modification at mitochondrial unfolded-protein-response genes.

Key Points Germ cells generate an organism's gametes and progeny. To accomplish this, germ cells must be properly specified and protected during development. In some animals, specification of the germline is continuous and involves the segregation of cytoplasmic 'determinants' during embryogenesis (preformation). In other animals, the germline is newly formed and requires inductive signalling during embryogenesis (induction). Among the diverse mechanisms of germ cell specification are: transmission of maternally supplied germ plasm containing germ granules to primordial germ cells (PGCs); transmission of epigenetic memory from parent germ cells to PGCs in progeny; and expression of transcription factors that programme embryonic cells to develop as PGCs. Aberrant gene expression or misguided PGC migration can cause germ cells to exhibit somatic features and even contribute to somatic tissues. In the gonad, germ cells are prevented from expressing genes that would threaten germline health and development. The mechanisms that suppress aberrant gene expression and protect germline fate include global transcriptional repression in PGCs, maintenance of a germline chromatin state and translation of only germline-appropriate transcripts in germ cells. Recent studies in different species have increased our understanding of the factors and molecular mechanisms that underlie the specification of germ cells, which are the specialized cells that generate gametes. Moreover, studies are elucidating how these cells ensure that only germline-appropriate transcripts are translated to protect germ cell identity. Germ cells are the special cells in the body that undergo meiosis to generate gametes and subsequently entire new organisms after fertilization, a process that continues generation after generation. Recent studies have expanded our understanding of the factors and mechanisms that specify germ cell fate, including the partitioning of maternally supplied 'germ plasm', inheritance of epigenetic memory and expression of transcription factors crucial for primordial germ cell (PGC) development. Even after PGCs are specified, germline fate is labile and thus requires protective mechanisms, such as global transcriptional repression, chromatin state alteration and translation of only germline-appropriate transcripts. Findings from diverse species continue to provide insights into the shared and divergent needs of these special reproductive cells.

As organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPR mt ) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPR mt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPR mt activation. The mitochondrial network expands to accommodate cell growth, but how scaling occurs is unclear. Here, the authors show in C. elegans that ATFS-1 mitochondrial import is reduced when mitochondrial proteins are highly expressed, activating the unfolded protein response and causing expansion.

A dual-view light sheet microscope allows high-speed imaging with an isotropic spatial resolution Optimal four-dimensional imaging requires high spatial resolution in all dimensions, high speed and minimal photobleaching and damage. We developed a dual-view, plane illumination microscope with improved spatiotemporal resolution by switching illumination and detection between two perpendicular objectives in an alternating duty cycle. Computationally fusing the resulting volumetric views provides an isotropic resolution of 330 nm. As the sample is stationary and only two views are required, we achieve an imaging speed of 200 images/s (i.e., 0.5 s for a 50-plane volume). Unlike spinning-disk confocal or Bessel beam methods, which illuminate the sample outside the focal plane, we maintain high spatiotemporal resolution over hundreds of volumes with negligible photobleaching. To illustrate the ability of our method to study biological systems that require high-speed volumetric visualization and/or low photobleaching, we describe microtubule tracking in live cells, nuclear imaging over 14 h during nematode embryogenesis and imaging of neural wiring during Caenorhabditis elegans brain development over 5 h.

The mechanism by which nutrient status regulates the fusion of autophagosomes with endosomes/lysosomes is poorly understood. Here, we report that O -linked β- N -acetylglucosamine ( O -GlcNAc) transferase (OGT) mediates O -GlcNAcylation of the SNARE protein SNAP-29 and regulates autophagy in a nutrient-dependent manner. In mammalian cells, OGT knockdown, or mutating the O -GlcNAc sites in SNAP-29, promotes the formation of a SNAP-29-containing SNARE complex, increases fusion between autophagosomes and endosomes/lysosomes, and promotes autophagic flux. In Caenorhabditis elegans , depletion of ogt-1 has a similar effect on autophagy; moreover, expression of an O -GlcNAc-defective SNAP-29 mutant facilitates autophagic degradation of protein aggregates. O -GlcNAcylated SNAP-29 levels are reduced during starvation in mammalian cells and in C. elegans . Our study reveals a mechanism by which O -GlcNAc-modification integrates nutrient status with autophagosome maturation. Zhang and colleagues report that starvation reduces O -GlcNAcylation of the SNARE protein SNAP-29. This promotes formation of a competent SNARE complex that increases autophagosome–lysosome fusion, increasing autophagosome maturation and flux.

RNA-mediated interference (RNAi) is a conserved mechanism that uses small RNAs (sRNAs) to silence gene expression. In the Caenorhabditis elegans germline, transcripts targeted by sRNAs are used as templates for sRNA amplification to propagate silencing into the next generation. Here we show that RNAi leads to heritable changes in the distribution of nascent and mature transcripts that correlate with two parallel sRNA amplification loops. The first loop, dependent on the nuclear Argonaute HRDE-1, targets nascent transcripts and reduces but does not eliminate productive transcription at the locus. The second loop, dependent on the conserved helicase ZNFX-1, targets mature transcripts and concentrates them in perinuclear condensates. ZNFX-1 interacts with sRNA-targeted transcripts that have acquired poly(UG) tails and is required to sustain pUGylation and robust sRNA amplification in the inheriting generation. By maintaining a pool of transcripts for amplification, ZNFX-1 prevents premature extinction of the RNAi response and extends silencing into the next generation. Ouyang et al. show that the RNA helicase ZNFX-1 preserves heritable RNAi by maintaining a pool of small RNA-targeted transcripts in perinuclear condensates of the Caenorhabditis elegans germline, which serve as templates for small-RNA amplification in the next generation.

In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 ( asah-1 ) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction. Wang et al. show that intestinal sphingosine-1-phosphate is transferred to oocytes and influences sphingolipid metabolism in the next generations. In the offspring, sphingosine-1-phosphate protects Caenorhabditis elegans neurons against axon fragility.

Intracellular transport depends on cooperation between distinct motor proteins. Two anterograde intraflagellar transport (IFT) motors, heterotrimeric kinesin-II and homodimeric OSM-3, cooperate to move cargo along Caenorhabditis elegans cilia. Here, using quantitative fluorescence microscopy, with single-molecule sensitivity, of IFT in living strains containing single-copy transgenes encoding fluorescent IFT proteins, we show that kinesin-II transports IFT trains through the ciliary base and transition zone to a ‘handover zone’ on the proximal axoneme. There, OSM-3 gradually replaces kinesin-II, yielding velocity profiles inconsistent with in vitro motility assays, and then drives transport to the ciliary tip. Dissociated kinesin-II motors undergo rapid turnaround and recycling to the ciliary base, whereas OSM-3 is recycled mainly to the handover zone. This reveals a functional differentiation in which the slower, less processive kinesin-II imports IFT trains into the cilium and OSM-3 drives their long-range transport, thereby optimizing cargo delivery. Using in vivo quantitative single-molecule fluorescence microscopy of kinesin II and OSM-3 motor dynamics in C. elegans cilia, Peterman and colleagues show that kinesin II loads cargo at the base, whereas OSM-3 transports the cargo to the tip.