bims-smemid 2026-03-29 papers

Protein Sci. 2026 Apr;35(4): e70537

From the cytosol to the inner membrane: biogenesis of the mitochondrial carrier family.

Catherine S Palmer, Phoebe J Leeming, Diana Stojanovski.

Mitochondrial carrier proteins are essential for cellular physiology as they are active in a wide range of metabolic pathways including production of cellular energy, amino acid synthesis, redox balance and ion homeostasis. The double membrane of mitochondria provides a tightly gated environment through which carrier proteins facilitate the exchange of substrates including nucleotides, ions, metabolites, cofactors and vitamins. The biogenesis of the carrier family relies on the coordinated action of the TOM and TIM22 complexes, which direct the translocation of nuclear-encoded precursors across the outer membrane (TOM) and their integration into the mitochondrial inner membrane (TIM22). Due to the intrinsic hydrophobicity of the carrier precursors, their import pathway requires chaperones in both the cytosol and intermembrane space to maintain solubility and prevent aggregation during transit. Given their central role in metabolism, dysfunction of the biogenesis machinery or the carrier proteins has serious consequences to human health. In this review we summarize the current understanding of carrier protein biogenesis in human cells and highlight how perturbations to this pathway influence human health.

Keywords: SLC25; TIM; TOM; citrin deficiency; mitochondrial carrier protein; protein biogenesis

DOI: https://doi.org/10.1002/pro.70537

Amino Acids. 2026 Mar 24.

Adaptive crosstalk between polyamine metabolism, translation, and autophagy sustains energy homeostasis in mammals during starvation: a scoping review.

Kayhan Karimi, Sigrid C Roberts, Nicola S Carter, Sebastian J Hofer, Reza Karimi.

Mammalian cells tightly regulate the shift between catabolism and anabolism to maintain energy homeostasis during starvation. Among other adaptations, cells adapt to nutrient restriction by downregulating translation, the most energy consuming cellular process, and inducing autophagy. Polyamines are ubiquitous small polycationic endogenous metabolites indispensable for cellular growth and viability. They regulate both autophagy and translation processes, coordinating an intriguing metabolic hub during cellular adaptation to starvation. Recent studies have highlighted a complex role for polyamines during starvation and a growing body of evidence underscores various nutrients and nutrient-sensing pathways that modulate autophagy through their influence on the mammalian target of rapamycin complex 1 (mTORC1) signaling. mTORC1 is a master regulator of cellular anabolism, including translation. Less explored is how these coordinated systems adapt and respond to starvation. This scoping review explores how changes in polyamine metabolism and related molecules orchestrate the adaptive crosstalk between autophagy, mTORC1, and translation to ensure that the mammalian cell conserves energy to maintain essential cellular functions during starvation. Our review highlights that spermidine and one of its major cellular targets, translation initiation factor 5A (eIF5A), facilitate translation of transcription factor EB (TFEB) to induce autophagy during starvation. Starvation suppresses mTORC1 activity, leading to reduced ribosome biogenesis and translation while promoting autophagy to meet cellular energy demands. We discuss the adaptive mechanisms by which reduced levels of acetyl-CoA, amino acids, EP300, glucose, insulin, and S-adenosylmethionine inhibit mTORC1 and simultaneously induce autophagy. Additionally, we describe the adaptive role that glucagon, Sestrin2, and urea play to inhibit mTORC1 and how eIF5A, glucagon, spermidine, and TFEB induce autophagy.

Keywords: Amino acids; Autophagy; Mammals; Spermidine; Translation; mTORC1

DOI: https://doi.org/10.1007/s00726-026-03512-6

Cell Rep. 2026 Mar 26. pii: S2211-1247(26)00235-4. [Epub ahead of print]45(4): 117157

Methionine metabolism is linked with phospholipid and glutamine metabolism to drive ferroptosis.

Ferroptosis is a lipid peroxidation-induced cell death mechanism that is regulated by amino acid metabolism. Cystine deprivation induces ferroptosis, but ferroptosis execution requires other amino acids. While methionine contributes to several metabolic pathways, including transsulfuration (TS), its role in ferroptosis remains controversial. Here, we report that methionine is required for ferroptosis triggered by cysteine deprivation. Notably, the TS pathway and methionine cycle in lung cancer cells are largely inactive, and methionine is instead funneled into polyamine synthesis via the methionine salvage route. Methionine depletion provokes metabolic shifts that dampen glutamine catabolism via the glutamine-methionine bi-cycle. Furthermore, methionine depletion alters phospholipid metabolism by promoting ACSL4 degradation, limiting polyunsaturated fatty acid (PUFA) incorporation into phospholipids. The methionine cycle intermediate S-adenosylmethionine (SAM) supplementation is sufficient to restore the perturbed metabolic state and ferroptosis sensitivity. Taken together, the results of this study highlight methionine as a key coordinator of ferroptosis through dynamic metabolic remodeling.

Keywords: ACSL4; CP: metabolism; CP: molecular biology; ferroptosis; glutaminolysis; methionine; methionine salvage pathway; phospholipid metabolism; transsulfuration pathway

DOI: https://doi.org/10.1016/j.celrep.2026.117157

Proteins. 2026 Mar 26.

Current Insight into Human Ornithine Aminotransferase: A Review.

Fulvio Floriani, Carla Borri Voltattorni, Riccardo Montioli.

Human ornithine aminotransferase (hOAT) is a mitochondrial matrix pyridoxal-5'-phosphate enzyme (PLP) that catalyzes the reversible transfer of the δ-amino group of L-ornithine (L-Orn) to α-ketoglutarate (α-KG) yielding glutamate-5-semialdehyde (GSA) and glutamate. GSA is prone to cyclize to Δ1-pyrroline-5-carboxylate. Human OAT holds significant clinical and scientific interest because (i) its dysfunction causes gyrate atrophy (GA) of the choroid and retina, a rare autosomal recessive disease, and (ii) it is recognized as a potential target for chemotherapeutic drug development, being overexpressed in some types of cancer. Here, we review the kinetic and structural features of the enzyme, as well as the mechanistic aspects of hOAT inhibition. Moreover, we focus our attention on the characterization of the structural and functional properties of the artificial variants and of those associated with GA. Considering that great progress toward the characterization of the pathogenic variants has been reached in the last few years, we summarize here, by revisiting the data available on the hOAT and its variants as purified recombinant form, the current understanding of (i) the molecular defect(s) of studied disease-causing mutations and (ii) the residues (particularly, active site residues critical for dictating the reaction specificity) and/or regions of the enzyme crucial for its folding and/or catalytic properties.

Keywords: molecular effects of mutations; ornithine aminotransferase; pathogenic variants; pyridoxal‐5′‐phosphate

DOI: https://doi.org/10.1002/prot.70134