Interfaces between organelles are emerging as critical platforms for many biological responses in eukaryotic cells. In yeast, the ERMES complex is an endoplasmic reticulum (ER)–mitochondria tether composed of four proteins, three of which contain a SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain. No functional ortholog for any ERMES protein has been identified in metazoans. Here, we identified PDZD8 as an ER protein present at ER-mitochondria contacts. The SMP domain of PDZD8 is functionally orthologous to the SMP domain found in yeast Mmm1. PDZD8 was necessary for the formation of ER-mitochondria contacts in mammalian cells. In neurons, PDZD8 was required for calcium ion (Ca2+) uptake by mitochondria after synaptically induced Ca2+-release from ER and thereby regulated cytoplasmic Ca2+ dynamics. Thus, PDZD8 represents a critical ER-mitochondria tethering protein in metazoans. We suggest that ER-mitochondria coupling is involved in the regulation of dendritic Ca2+ dynamics in mammalian neurons.

Aging determinants are asymmetrically distributed during cell division in S. cerevisiae, which leads to production of an immaculate, age-free daughter cell. During this process, damaged components are sequestered and retained in the mother cell, and higher functioning organelles and rejuvenating factors are transported to and/or enriched in the bud. Here, we will describe the key quality control mechanisms in budding yeast that contribute to asymmetric cell division of aging determinants including mitochondria, endoplasmic reticulum (ER), vacuoles, extrachromosomal rDNA circles (ERCs), and protein aggregates.

Previous studies indicate that replicative lifespan in daughter cells of Sacchraromyces cerevisiae depends on the preferential inheritance of young, high-functioning mitochondria. We report here that mitochondria are functionally segregated even within single mother cells in S. cerevisiae. A high-functioning population of mitochondria accumulates at the tip of the mother cell distal to the bud. We find that the mitochondrial F-box protein (Mfb1p) localizes to mitochondria in the mother tip and is required for mitochondrial anchorage at that site, independent of the previously identified anchorage protein Num1p. Deletion of MFB1 results in loss of the mother-tip-localized mitochondrial population, defects in mitochondrial function and premature replicative ageing. Inhibiting mitochondrial inheritance to buds, by deletion of MMR1, in mfb1Δ cells restores mitochondrial distribution, promotes mitochondrial function and extends replicative lifespan. Our results identify a mechanism that retains a reservoir of high-functioning mitochondria in mother cells and thereby preserves maternal reproductive capacity.

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Tethers that link mitochondria to other organelles are critical for lipid and calcium transport as well as mitochondrial genome replication and fission of the organelle. Here, we review recent advances in the characterization of interorganellar mitochondrial tethers in the budding yeast, Saccharomyces cerevisiae. We specifically focus on evidence for a role for mitochondrial tethers that anchor mitochondria to specific regions within yeast cells. These tethering events contribute to two processes that are critical for normal replicative lifespan: inheritance of fitter mitochondria by daughter cells, and retention of a small pool of higher-functioning mitochondria in mother cells. Since asymmetric inheritance of mitochondria also occurs in human mammary stem-like cells, it is possible that mechanisms underlying mitochondrial segregation in yeast also operate in other cell types.

Accurately quantifying cellular morphology at scale could substantially empower existing single-cell approaches. However, measuring cell morphology remains an active field of research, which has inspired multiple computer vision algorithms over the years. Here, we show that DINO, a vision-transformer based, self-supervised algorithm, has a remarkable ability for learning rich representations of cellular morphology without manual annotations or any other type of supervision. We evaluate DINO on a wide variety of tasks across three publicly available imaging datasets of diverse specifications and biological focus. We find that DINO encodes meaningful features of cellular morphology at multiple scales, from subcellular and single-cell resolution, to multi-cellular and aggregated experimental groups. Importantly, DINO successfully uncovers a hierarchy of biological and technical factors of variation in imaging datasets. The results show that DINO can support the study of unknown biological variation, including single-cell heterogeneity and relationships between samples, making it an excellent tool for image-based biological discovery.

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Babies are born young, largely independent of the age of their mothers. Mother-daughter age asymmetry in yeast is achieved, in part, by inheritance of higher-functioning mitochondria by daughter cells and retention of some high-functioning mitochondria in mother cells. The mitochondrial F-box protein, Mfb1p, tethers mitochondria at both poles in a cell cycle-regulated manner: it localizes to and anchors mitochondria to the mother cell tip throughout the cell cycle, and to the bud tip prior to cytokinesis. Here, we report that cell polarity and polarized localization of Mfb1p decline with age in S. cerevisiae. Moreover, deletion of BUD1/RSR1, a Ras protein required for cytoskeletal polarization during asymmetric yeast cell division, results in depolarized Mfb1p localization, defects in mitochondrial distribution and quality control, and reduced replicative lifespan. Our results demonstrate a role for the polarity machinery in lifespan through modulating Mfb1 function in asymmetric inheritance of mitochondria during yeast cell division.