SLC25A39 binds and modulates PRDX1 to suppress ROS-induced necroptosis in hepatocellular carcinoma.

MSDC-0160, a novel clinical-stage mitochondrial pyruvate carrier inhibitor, suppresses osteoclast differentiation and alleviates type 2 diabetes-related bone loss.

Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.

Short-term black carbon exposure impairs mental health and DNA methylation signatures of mitochondrial carrier genes.

Elevated cerebrospinal fluid 2-Hydroxybutyric acid in two siblings with aspartate-glutamate carrier 1 deficiency.

SLC25A mitochondrial carriers as biomarkers and therapeutic targets of spaceflight-induced dysfunction: the ADP/ATP carrier (AAC3) as a structural case study.

BackgroundHepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent demand for novel diagnostic and therapeutic targets. While mitochondrial carriers (MCs) play crucial roles in tumor metabolism, their specific contributions to HCC pathogenesis are poorly understood.MethodsBy leveraging multi-omics analyses, including single-cell sequencing and spatial transcriptomics, SLC25A39 was identified as a key mitochondrial carrier in HCC. To assess its diagnostic potential, receiver operating characteristic (ROC) curves were constructed across multiple retrospective independent cohorts. Functional experiments of HCC cell lines with SLC25A39 knockdown were conducted in vitro (cell proliferation, Transwell migration and invasion, and apoptosis assays) and in vivo (xenograft experiments). For deeper mechanistic insights, we employed proteomic profiling and mitochondrial functional assays. Additionally, the mitochondrial-targeted antioxidant (2-oxo-2-((2,2,6,6-tetramethyl-1-oxyl-piperidin-4-yl)amino)ethyl)triphenylphosphonium chloride (mitoTEMPO) was employed to reverse the observed phenotypes.ResultsSLC25A39 exhibited significant overexpression in HCC tissues, particularly in advanced-stage tumors, and demonstrated robust diagnostic accuracy (area under the curve (AUC) > 0.900 across cohorts). Deficiency of SLC25A39 markedly reduced HCC cell proliferation, migration, and invasion capabilities, triggering caspase-9/3-dependent apoptosis. Consistent with in vitro findings, xenograft models revealed impaired tumor growth upon SLC25A39 suppression. Mechanistically, SLC25A39 deficiency induced mitochondrial dysfunction, characterized by excessive mitochondrial reactive oxygen species (ROS), reduced membrane potential, diminished adenosine triphosphate (ATP) synthesis, aberrant mitochondrial permeability transition pore (mPTP) opening, and cytochrome c release. Notably, mitoTEMPO treatment reversed these effects, restoring mitochondrial redox homeostasis and rescuing malignant phenotypes.ConclusionsOur study reveals SLC25A39 as a critical regulator of HCC progression via the mitochondrial ROS-cytochrome c-caspase signaling axis, highlighting its potential as a diagnostic biomarker and therapeutic target in HCC.Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1186/s11658-025-00829-0.

High-energy-demanding tissues, such as skeletal muscle, rely on mitochondrial proteostasis for proper function. Two key quality-control mechanisms -the ubiquitin proteasome system (UPS) and the release of mitochondria-derived vesicles- help maintain mitochondrial proteostasis, but whether these processes interact remains unclear. Here, we show that CRL5Ozz and its substrate, Alix, localize to mitochondria and together regulate the levels and distribution of the mitochondrial solute carrier Slc25A4, which is essential for ATP production. In Ozz-/- or Alix-/- mice, skeletal muscle mitochondria exhibit similar morphological abnormalities, including swelling and dysmorphism, along with partially overlapping metabolomic alterations. We demonstrate that CRL5Ozz ubiquitinates Slc25A4, targeting it for proteasomal degradation, while Alix facilitates Slc25A4 loading into exosomes for lysosomal degradation. Loss of Ozz or Alix in vivo disrupts the steady-state levels of Slc25A4, impairing mitochondrial metabolism and triggering a switch in muscle fiber composition from oxidative, mitochondria-rich slow to glycolytic fast fibers.

Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by GLP1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.

AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.

Structural transport and inhibition mechanism of the mitochondrial pyruvate carrier.

p38 MAPK-mediated suppression of Nrf2-MPC2 axis drives metabolic reprogramming which confers imatinib resistance in blast crisis phase of chronic myeloid leukemia.

Structural dynamics of the mitochondrial ADP/ATP carrier support an asymmetric transport mechanism.

The high demand for energy during floral thermogenesis drives the synergistic operation of multiple energy substrates for the rapid temperature rise and successful reproduction of flowers. However, how thermogenic plants precisely regulate substrate supply and metabolic pathways within a short time to support large-scale energy and heat release remains a mystery. This study revealed the elaborate synergistic supply mechanism of multi-source substrates in Magnolia denudata during thermogenesis. Transcriptome analysis showed that genes related to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) were significantly upregulated during the thermogenic stage (S2). Mitochondrial feeding assays using isotopically labelled substrates revealed that during the thermogenic stage, both the amount of pyruvate imported via the mitochondrial pyruvate carrier (MPC) and NAD-malic enzyme (NAD-ME) increased, and their synergistic effect accelerated the metabolic flow of the TCA cycle. Targeted lipidomics analysis indicated that the content of 63.6% fatty acids in the fatty acid degradation pathway decreased, while the key enzyme genes involved in triacylglycerol lipase (TGL) and fatty acid β-oxidation pathways were highly expressed during the thermogenic stage. In addition, enhanced expression of genes related to alanine aminotransferase (AlaAT) and glutamate dehydrogenase (GDH) suggested that amino acid metabolism might provide additional substrates for thermogenesis. This study clarifies the synergistic energy supply of carbohydrate, fatty acid and amino acid metabolism during thermogenesis in M. denudata, providing new evidence for understanding the metabolic regulatory flexibility of floral thermogenesis in plants.

IntroductionAdenine nucleotide translocase (ANT), phosphate translocase (PiT), and uncoupling proteins (UCPs), all integral to oxidative phosphorylation, are among the carrier proteins of the mitochondrial inner membrane (MIM). While traditionally thought to function as monomers, their close proximity within the densely packed MIM suggests potential mutual interactions and formation of homo- and/or hetero-oligomers, the physiological implications of which are yet to be understood.MethodsWe investigated the conformations and proton transport activity of ANT1, PiT, UCP2 and UCP4 individually and in combination, to explore the possibility of hetero-oligomerization and functionally relevant interactions among the proteins. Monomeric proteins were reconstituted, individually and/or in combination, into model lipid membranes and the conformation, oligomeric state, and proton transport activities were assessed using biophysical approaches.ResultsUCP2 and UCP4 spontaneously assembled into functional tetramers, whereas ANT1 and PiT predominantly remained monomeric. The presence of cardiolipin in lipid membranes affected ANT1 oligomerization but had no influence on UCPs or PiT, suggesting that homotetramerization may be a characteristic of only a subset of mitochondrial carriers. Nevertheless, binary and ternary combinations of the proteins formed heterotetramers capable of proton transport. The UCP2-ANT1 combination showed significant proton transport, whereas proton transport by the UCP4-PiT combination was substantially lower, highlighting the specificity of interactions. Proton transport was differentially activated by free fatty acids; oleic acid was a better activator than palmitic acid. Inhibitory effects of purine nucleotides also varied across different protein combinations.DiscussionCollectively, our findings emphasize how interactions among these four mitochondrial carrier proteins may affect proton transport across the MIM and influence mitochondrial bioenergetics.

SLC25A51 is required for the replenishment of free nicotinamide adenine dinucleotide (oxidized form) (NAD+) into mammalian mitochondria. However, it is not known how SLC25A51 imports this anionic molecule to sustain elevated NAD+ concentrations in the matrix. Understanding this would reveal regulatory mechanisms used to maintain critical bioenergetic gradients for cellular respiration, oxidative mitochondrial reactions, and mitochondrial adenosine triphosphate (ATP) production. In this work, mutational analyses and localized NAD+ biosensors revealed that the mitochondrial membrane potential (ΔΨm) works in concert with charged residues in the carrier’s inner pore to enable sustained import of NAD+ against its electrochemical gradient into the matrix. Dissipation of the ΔΨm or mutation of select residues in SLC25A51 led to equilibration of NAD+ from the matrix. Corroborating data were obtained with the structurally distinct mitochondrial NAD+ carrier from Saccharomyces cerevisiae (ScNdt1p) and mitochondrial ATP transport suggesting a shared mechanism of charge compensation and electrogenic transport in these mitochondrial carrier family members.

Copper is an essential trace element required for mitochondrial respiration and cellular metabolism, yet its role in skeletal muscle remains incompletely understood. Here, we show that skeletal muscle-specific deletion of the high-affinity copper importer Ctr1 (SMKO) in mice leads to copper deficiency, resulting in exercise intolerance, metabolic dysfunction, and hallmarks of mitochondrial myopathy, including ragged-red fibers, lactic acidosis, and aberrant mitochondrial morphology. Copper deficiency disrupted electron transport chain proteome and induced mitochondrial hyperfusion. We identified mitochondrial carrier homolog 2 (MTCH2), an outer mitochondrial membrane protein, as a copper-binding regulator of mitochondrial copper distribution and morphology. Restoring copper levels via the copper ionophore or AAV-mediated Ctr1 re-expression rescued mitochondrial function and alleviated myopathic features in SMKO. These findings highlight MTCH2 as a key mediator of a critical link between copper homeostasis and mitochondrial remodeling required for skeletal muscle function.

Intracellular vacuolar pathogens replicate within membrane-bound compartments known as pathogen-containing vacuoles (PCVs). Maintaining the integrity of these vacuoles is essential for creating a permissive niche that supports pathogen survival and proliferation. In this study, we show that Salmonella enterica serovar Typhimurium co-opts the host mitochondrial citrate carrier (CIC) to promote its intracellular replication by detoxifying the Salmonella-containing vacuole (SCV). Loss of CIC significantly impairs Salmonella growth within host cells, as CIC recruitment to SCVs regulates local citrate levels and mitigates the production of reactive oxygen species (ROS), thereby reducing oxidative stress. Mechanistically, we identify the SPI-2 effector SseF as a critical factor that interacts with CIC and the GTPase RAB7, enabling CIC recruitment to the SCV membrane. These findings reveal a previously unrecognized strategy by which an intracellular pathogen hijacks a mitochondrial metabolite transporter to modulate the vacuolar environment and evade host antimicrobial defenses. Notably, pharmacological inhibition of CIC sensitizes Salmonella to host immune pressures, highlighting CIC as a potential target for host-directed antimicrobial therapy.

Myasthenia gravis (MG) is an autoimmune disorder mediated by B-cells, characterized by muscle weakness and fatigue. Mitochondria, essential for energy production and muscle function, have been implicated in MG. Despite their importance, the exact relationship between mitochondrial proteins (MPs) and MG remains unclear. This study utilized two-sample Mendelian Randomization (TSMR) to investigate potential causal associations between MPs and MG. Data from the largest available genome-wide associated study (GWAS), comprising 1873 acetylcholine receptor (AchR) antibody-positive MG patients (1278 late-onset MG [LOMG] and 595 early-onset MG [EOMG]), were analyzed. A total of 66 MPs were selected as exposure variables, with MG and its subtypes as outcomes. Analyses employed inverse variance weighted (IVW), MR-PRESSO, MR-Egger, and weighted median methods, with heterogeneity assessed using Cochran’s Q statistic. Significant causal associations were found between MPs and MG subtypes. For LOMG, GrpE protein homolog 1, oligoribonuclease, protein SCO1 homolog, and rRNA methyltransferase 3 were linked to increased risk. Cytochrome c oxidase subunit 7A1 was associated with higher EOMG risk, while [pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, dihydrolipoyl dehydrogenase, and NFU1 iron-sulfur cluster scaffold were linked to reduced EOMG risk. MPs such as dihydrolipoyl dehydrogenase and NAD-dependent protein deacylase sirtuin-5 showed protective effects against MG, while GrpE protein homolog 1, mitochondrial glutamate carrier 2, oligoribonuclease, and protein SCO1 homolog were associated with increased risk. This MR analysis suggests potential causal relationships between MPs and MG, highlighting the need for further research to validate these findings and explore the mechanisms underlying these associations.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-22607-w.

SIRT3 deficiency aggravates mitochondrial metabolic disorder and podocyte injury in DKD via MPC2 acetylation.