David M. Sabatini

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent …

Lysosomes are active sites to integrate cellular metabolism and signal transduction. A collection of proteins associated with the lysosome mediate these metabolic and signaling functions. Both lysosomal metabolism and lysosomal signaling have been linked to longevity regulation; however, how lysosomes adjust their protein composition to accommodate this regulation remains unclear. Using deep proteomic profiling, we systemically profiled lysosome-associated proteins linked with four different longevity mechanisms. We discovered the lysosomal recruitment of AMPK and nucleoporin proteins and their requirements for longevity in response to increased lysosomal lipolysis. Through comparative proteomic analyses of lysosomes from different tissues and labeled with different markers, we further elucidated lysosomal heterogeneity across tissues as well as the increased enrichment of the Ragulator complex on Cystinosin positive lysosomes. Together, this work uncovers lysosomal proteome heterogeneity across multiple scales and provides resources for understanding the contribution of lysosomal protein dynamics to signal transduction, organelle crosstalk and organism longevity.

Disclosed herein are methods and compositions for modulating MFSD12 expression and activity to treat diseases such as lysosomal storage diseases, including cystinosis. Also disclosed are methods of altering skin pigmentation and methods of screening for MFSD12 modulation agents.

Aspects of the present disclosure provide compositions comprising NEK10 for example, wild-type NEK10 or a hyper-active NEK10 mutant such as NEK10 S684D, and methods of using such for treating a respiratory disorder such as bronchiectasis.

In some aspects, described herein are cell culture media that are useful for in vitro culture of mammalian cells. The culture media contain a variety of small organic compounds that are found in normal adult human blood. Also described are methods of using the culture media for a variety of purposes. Also described are methods of treating cancer.

In some aspects, the disclosure provides methods for modulating mitochondrial transport of serine in a cell, the methods comprising modulating expression or activity of one or more sideroflexins. In some aspects, methods of identifying agents that modulate sideroflexin expression or activity are provided. In some aspects, methods of treating cancer are provided.

Author Correction: Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila Author Correction: Sestrin mediates detection of and adaptation to low-leucine diets in Drosophila Nature. 2022 Sep;609(7929):E11. doi: 10.1038/s41586-022-05286-9. Authors Xin Gu # 1 2 , Patrick Jouandin # 3 4 , Pranav V Lalgudi 5 6 , Rich Binari 7 8 , Max L Valenstein 5 6 , Michael A Reid 9 , Annamarie E Allen 9 , Nolan Kamitaki 7 10 11 , Jason W Locasale 9 , Norbert Perrimon 12 13 , David M Sabatini Affiliations 1 Whitehead Institute for Biomedical Research, Cambridge, MA, USA. xingu@mit.edu. 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. xingu@mit.edu. 3 Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. Patrick_Jouandin@hms.harvard.edu. 4 Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA. …