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For many nuclear-encoded mitochondrial genes, mRNA localizes to the mitochondrial surface co-translationally, aided by the association of a mitochondrial targeting sequence (MTS) on the nascent peptide with the mitochondrial import complex. For a subset of these co-translationally localized mRNAs, their localization is dependent on the metabolic state of the cell, while others are constitutively localized. To explore the differences between these two mRNA types we developed a stochastic, quantitative model for MTS-mediated mRNA localization to mitochondria in yeast cells. This model includes translation, applying gene-specific kinetics derived from experimental data; and diffusion in the cytosol. Even though both mRNA types are co-translationally localized we found that the steady state number, or density, of ribosomes along an mRNA was insufficient to differentiate the two mRNA types. Instead, conditionally-localized mRNAs have faster translation kinetics which modulate localization in combination with changes to diffusive search kinetics across metabolic states. Our model also suggests that the MTS requires a maturation time to become competent to bind mitochondria. Our work indicates that yeast cells can regulate mRNA localization to mitochondria by controlling mitochondrial volume fraction (influencing diffusive search times) and gene translation kinetics (adjusting mRNA binding competence) without the need for mRNA-specific binding proteins. These results shed light on both global and gene-specific mechanisms that enable cells to alter mRNA localization in response to changing metabolic conditions. 

Abstract Several organelles in eukaryotic cells, including mitochondria and the endoplasmic reticulum, form interconnected tubule networks extending throughout the cell. These tubular networks host many biochemical pathways that rely on proteins diffusively searching through the network to encounter binding partners or localized target regions. Predicting the behavior of such pathways requires a quantitative understanding of how confinement to a reticulated structure modulates reaction kinetics. In this work, we develop both exact analytical methods to compute mean first passage times and efficient kinetic Monte Carlo algorithms to simulate trajectories of particles diffusing in a tubular network. Our approach leverages exact propagator functions for the distribution of transition times between network nodes and allows large simulation time steps determined by the network structure. The methodology is applied to both synthetic planar networks and organelle network structures, demonstrating key general features such as the heterogeneity of search times in different network regions and the functional advantage of broadly distributing target sites throughout the network. The proposed algorithms pave the way for future exploration of the interrelationship between tubular network structure and biomolecular reaction kinetics. Graphic Abstract 

Abstract Eukaryotic cells face the challenging task of transporting a variety of particles through the complex intracellular milieu in order to deliver, distribute, and mix the many components that support cell function. In this review, we explore the biological objectives and physical mechanisms of intracellular transport. Our focus is on cytoplasmic and intra-organelle transport at the whole-cell scale. We outline several key biological functions that depend on physically transporting components across the cell, including the delivery of secreted proteins, support of cell growth and repair, propagation of intracellular signals, establishment of organelle contacts, and spatial organization of metabolic gradients. We then review the three primary physical modes of transport in eukaryotic cells: diffusive motion, motor-driven transport, and advection by cytoplasmic flow. For each mechanism, we identify the main factors that determine speed and directionality. We also highlight the efficiency of each transport mode in fulfilling various key objectives of transport, such as particle mixing, directed delivery, and rapid target search. Taken together, the interplay of diffusion, molecular motors, and flows supports the intracellular transport needs that underlie a broad variety of biological phenomena. 

The sorting of proteins into different functional compartments is a fundamental cellular task. In this issue, Maza et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201906024) demonstrate that distinct protein populations are dynamically generated in specialized regions of photoreceptors via an interplay of protein-membrane affinity, impeded diffusion, and driven transport.