bims-mimbat 2024-07-14 papers

Dev Cell. 2024 Jul 03. pii: S1534-5807(24)00386-1. [Epub ahead of print]

Slc25a3-dependent copper transport controls flickering-induced Opa1 processing for mitochondrial safeguard.

Daisuke Murata, Shubhrajit Roy, Svetlana Lutsenko, Miho Iijima, Hiromi Sesaki.

Following the Goldilocks principle, mitochondria size must be "just right." Mitochondria balance division and fusion to avoid becoming too big or too small. Defects in this balance produce dysfunctional mitochondria in human diseases. Mitochondrial safeguard (MitoSafe) is a defense mechanism that protects mitochondria against extreme enlarging by suppressing fusion in mammalian cells. In MitoSafe, hyperfused mitochondria elicit flickering-short pulses of mitochondrial depolarization. Flickering activates an inner membrane protease, Oma1, which in turn proteolytically inactivates a mitochondrial fusion protein, Opa1. The mechanisms underlying flickering are unknown. Using a live-imaging screen, we identified Slc25a3 (a mitochondrial carrier transporting phosphate and copper) as necessary for flickering and Opa1 cleavage. Remarkably, copper, but not phosphate, is critical for flickering. Furthermore, we found that two copper-containing mitochondrial enzymes, superoxide dismutase 1 and cytochrome c oxidase, regulate flickering. Our data identify an unforeseen mechanism linking copper, redox homeostasis, and membrane flickering in mitochondrial defense against deleterious fusion.

Keywords: division; fusion; mitochondria; stress response; transporter

DOI: https://doi.org/10.1016/j.devcel.2024.06.008

J Am Chem Soc. 2024 Jul 11.

Dynamic Second Harmonic Imaging of Proton Translocation Through Water Needles in Lipid Membranes.

Seonwoo Lee, Chetan S Poojari, Anna Maznichenko, David Roesel, Iwona Swiderska, Peter Pohl, Jochen S Hub, Sylvie Roke.

Proton translocation through lipid membranes is a fundamental process in the field of biology. Several theoretical models have been developed and presented over the years to explain the phenomenon, yet the exact mechanism is still not well understood. Here, we show that proton translocation is directly related to membrane potential fluctuations. Using high-throughput wide-field second harmonic (SH) microscopy, we report apparently universal transmembrane potential fluctuations in lipid membrane systems. Molecular simulations and free energy calculations suggest that H+ permeation proceeds predominantly across a thin, membrane-spanning water needle and that the transient transmembrane potential drives H+ ions across the water needle. This mechanism differs from the transport of other cations that require completely open pores for transport and follows naturally from the well-known Grotthuss mechanism for proton transport in bulk water. Furthermore, SH imaging and conductivity measurements reveal that the rate of proton transport depends on the structure of the hydrophobic core of bilayer membranes.

DOI: https://doi.org/10.1021/jacs.4c02810

J Gen Physiol. 2024 Aug 05. pii: e202413554. [Epub ahead of print]156(8):

Mathematical modeling of intracellular osmolarity and cell volume stabilization: The Donnan effect and ion transport.

Zahra Aminzare, Alan R Kay.

The presence of impermeant molecules within a cell can lead to an increase in cell volume through the influx of water driven by osmosis. This phenomenon is known as the Donnan (or Gibbs-Donnan) effect. Animal cells actively transport ions to counteract the Donnan effect and regulate their volume, actively pumping Na+ out and K+ into their cytosol using the Na+/K+ ATPase (NKA) pump. The pump-leak equations (PLEs) are a system of algebraic-differential equations to model the membrane potential, ion (Na+, K+, and Cl-), and water flux across the cell membrane, which provide insight into how the combination of passive ions fluxes and active transport contribute to stabilizing cell volume. Our broad objective is to provide analytical insight into the PLEs through three lines of investigation: (1) we show that the provision of impermeant extracellular molecules can stabilize the volume of a passive cell; (2) we demonstrate that the mathematical form of the NKA pump is not as important as the stoichiometry for cell stabilization; and (3) we investigate the interaction between the NKA pump and cation-chloride co-transporters (CCCs) on cell stabilization, showing that NCC can destabilize a cell while NKCC and KCC can stabilize it. We incorporate extracellular impermeant molecules, NKA pump, and CCCs into the PLEs and derive the exact formula for the steady states in terms of all the parameters. This analytical expression enables us to easily explore the effect of each of the system parameters on the existence and stability of the steady states.

DOI: https://doi.org/10.1085/jgp.202413554

Nat Genet. 2024 Jul 08.

Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import.

Artem Khan, Gokhan Unlu, Phillip Lin, Yuyang Liu, Ece Kilic, Timothy C Kenny, Kıvanç Birsoy, Eric R Gamazon.

Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Association Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions and even pinpoint genes that are distant from the variants implicated by GWAS. In particular, our analysis identified solute carrier family 25 member 48 (SLC25A48) as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite betaine. Integrative rare variant and polygenic score analyses in UK Biobank provide strong evidence that the SLC25A48 causal effects on human disease may in part be mediated by the effects of choline. Altogether, our study provides a discovery platform for metabolic gene function and proposes SLC25A48 as a mitochondrial choline transporter.

DOI: https://doi.org/10.1038/s41588-024-01827-2

Cell Rep. 2024 Jul 05. pii: S2211-1247(24)00754-X. [Epub ahead of print]43(7): 114425

Engineering an energy-dissipating hybrid tissue in vivo for obesity treatment.

Lintao Wang, Yajie Sun, Lifang Yang, Shaocong Wang, Chunyan Liu, Yulian Wang, Yiming Niu, Zhen Huang, Junfeng Zhang, Chunming Wang, Lei Dong.

Obesity is a global health challenge with limited therapeutic solutions. Here, we demonstrate the engineering of an energy-dissipating hybrid tissue (EDHT) in the body for weight control. EDHT is constructed by implanting a synthetic gel matrix comprising immunomodulatory signals and functional cells into the recipient mouse. The immunomodulatory signals induce the host stromal cells to create an immunosuppressive niche that protects the functional cells, which are overexpressing the uncoupling protein 1 (UCP1), from immune rejection. Consequently, these endogenous and exogenous cells co-develop a hybrid tissue that sustainedly produces UCP1 to accelerate the host's energy expenditure. Systematic experiments in high-fat diet (HFD) and transgenic (ob/ob) mice show that EDHT efficiently reduces body weight and relieves obesity-associated pathological conditions. Importantly, an 18-month observation for safety assessment excludes cell leakage from EDHT and reports no adverse physiological responses. Overall, EDHT demonstrates convincing efficacy and safety in controlling body weight.

Keywords: CP: Metabolism; UCP1; artificial organ; diabetes; high-fat diet; obesity; uncoupling

DOI: https://doi.org/10.1016/j.celrep.2024.114425