bims-mimbat 2025-05-25 papers

Acta Physiol (Oxf). 2025 Jun;241(6): e70056

Mitochondrial Bioenergetics in Physiology.

Keywords: bioenergetics; brown adipose tissue; disease; ectothermic; endothermic; mitochondria; sarcopenia; ucp1

Nature. 2025 May 21.

Stepwise ATP translocation into the endoplasmic reticulum by human SLC35B1.

Ashutosh Gulati, Do-Hwan Ahn, Albert Suades, Yurie Hult, Gernot Wolf, So Iwata, Giulio Superti-Furga, Norimichi Nomura, David Drew.

ATP generated in the mitochondria is exported by an ADP/ATP carrier of the SLC25 family1. The endoplasmic reticulum (ER) cannot synthesize ATP but must import cytoplasmic ATP to energize protein folding, quality control and trafficking2,3. It was recently proposed that a member of the nucleotide sugar transporter family, termed SLC35B1 (also known as AXER), is not a nucleotide sugar transporter but a long-sought-after ER importer of ATP4. Here we report that human SLC35B1 does not bind nucleotide sugars but indeed executes strict ATP/ADP exchange with uptake kinetics consistent with the import of ATP into crude ER microsomes. A CRISPR-Cas9 cell-line knockout demonstrated that SLC35B1 clusters with the most essential SLC transporters for cell growth, consistent with its proposed physiological function. We have further determined seven cryogenic electron microscopy structures of human SLC35B1 in complex with an Fv fragment and either bound to an ATP analogue or ADP in all major conformations of the transport cycle. We observed that nucleotides were vertically repositioned up to approximately 6.5 Å during translocation while retaining key interactions with a flexible substrate-binding site. We conclude that SLC35B1 operates by a stepwise ATP translocation mechanism, which is a previously undescribed model for substrate translocation by an SLC transporter.

DOI: https://doi.org/10.1038/s41586-025-09069-w

J Biol Chem. 2025 May 14. pii: S0021-9258(25)02087-3. [Epub ahead of print] 110237

ABHD18 degrades cardiolipin by stepwise hydrolysis of fatty acids.

Mindong Ren, Shiyu Chen, Miriam L Greenberg, Michael Schlame.

Cardiolipin (CL), the signature phospholipid of mitochondria, carries four fatty acids that are remodeled after de novo synthesis. In yeast, remodeling is accomplished by the joint action of Cld1, a lipase that removes a fatty acid from CL, and Taz1, a transacylase that transfers a fatty acid from another phospholipid to monolyso-CL. While taz1 homologues have been identified in all eukaryotes, cld1 homologues have remained obscure. Here we demonstrate that ABHD18, a highly conserved protein of plants, animals, and humans, is functionally homologous to Cld1. Knockdown of Abhd18 decreased the concentration of monolyso-CL in murine, Taz-knockout myoblasts. Inactivation of Abhd18 in Drosophila substantially increased the abundance of CL. Abhd18 inactivation also reversed the increase in the rate of CL degradation, as measured with 13C isotopes, and the accumulation of deacylated CLs, such as monolyso-CL and dilyso-CL, in TAZ-deficient flies. CL species with more than 5 double bonds were resistant to ABHD18. Our data demonstrate that ABHD18 is the elusive lipase that hydrolyzes CL in mice and flies and presumably in other organisms. Rather than removing just one fatty acid, we show that ABHD18 deacylates CL further. Thus, ABHD18 catalyzes the breakdown of CL whereas TAZ protects CL from degradation.

Keywords: cardiolipin; lipase; lysophospholipid; mitochondria; phospholipid turnover; tafazzin

DOI: https://doi.org/10.1016/j.jbc.2025.110237

Biophys J. 2025 May 19. pii: S0006-3495(25)00312-1. [Epub ahead of print]

The molecular mechanism of ATP synthase constrains the evolutionary landscape of chemiosmosis.

J Emyr Macdonald, Paul D Ashby.

ATP synthase, the enzyme responsible for regenerating adenosine triphosphate (ATP) in the cell, comprises a proton-translocating motor in the cell membrane (labelled FO in bacteria, mitochondria and chloroplasts), coupled by a common stalk to a catalytic motor F1 that synthesises or hydrolyses ATP, depending on the direction of rotation. The detailed mechanisms of FO, F1 and their coupling in ATP synthase have been elucidated through structural studies, single molecule experiments and molecular modelling. The outcomes of this body of work are reviewed with a particular focus on the features of the mechanism that enable the high energy efficiency and reversibility of ATP synthase. Models for the origin of chemiosmosis involve either ATP synthesis (driven by the proton gradient across the membrane) or ATP hydrolysis (for pumping protons out of the cell) as a primary function, the other function being a later development enabled by the coupled nature of the two motors. The mechanism of ATP synthase and the stringent requirements on efficiency to maintain life constrains existing models and the search for the origin of chemiosmosis.

Keywords: ATP hydrolysis; ATP synthase; biomolecular motors; chemiosmosis; chemo-mechanical coupling; proton gradients; torque generation

DOI: https://doi.org/10.1016/j.bpj.2025.05.017

Cell. 2025 May 17. pii: S0092-8674(25)00506-9. [Epub ahead of print]

Inheritance of acquired adaptive cold tolerance in rice through DNA methylation.

Xianwei Song, Shanjie Tang, Hui Liu, Ying Meng, Haofei Luo, Bao Wang, Xiu-Li Hou, Bin Yan, Chao Yang, Zhenhua Guo, Lizhi Wang, Shukun Jiang, Xian Deng, Xiaofeng Cao.

Epigenetic pathways could provide a mechanistic explanation for the inheritance of acquired characteristics, as proposed by Lamarck in 1802, but epigenetic alterations that endow adaptive hereditary traits have rarely been observed. Here, in cultivated Asian rice (Oryzasativa L.), we identified an epiallele conferring acquired and heritable cold tolerance, an adaptive trait enabling northward spread from its tropical origins. We subjected cold-sensitive rice to multigenerational cold stress and identified a line with acquired stable inheritance of cold tolerance. DNA-hypomethylation variation in the acquiredcoldtolerance 1 (ACT1) promoter region rendered its expression insensitive to cold. This change is, in large part, responsible for the acquired cold tolerance, as confirmed by DNA-methylation editing. Natural variation in ACT1 DNA hypomethylation is associated with cold tolerance and rice geographic distribution. Hypomethylation at ACT1 triggers adaptive cold tolerance, presenting a route to epigenetic-variation-driven inheritance of acquired characteristics.

Keywords: DNA methylation; cold tolerance; inheritance of acquired characteristics; natural epigenetic variation; rice

DOI: https://doi.org/10.1016/j.cell.2025.04.036