The protein at the center of the study is adenine nucleotide translocase 3, or ANT3, a transporter embedded in the inner mitochondrial membrane that normally shuttles ATP out of the mitochondrial matrix in exchange for ADP from the cytosol. Beyond its day job as an exchange factor, ANT3 has long been implicated as a core constituent of the mitochondrial permeability transition pore, or mPTP, a high-conductance channel whose opening dissipates the proton gradient that powers ATP synthesis, swells the mitochondria, and can launch cell death. Disruption of ANT3 protein homeostasis, or conformational changes in the protein itself, are sufficient to trigger this catastrophic opening. What has remained murky is how the cell regulates ANT3’s abundance and shape in the first place, and that is precisely the question the Chongqing group set out to answer.

The researchers’ starting point was prolonged starvation, a physiological stress that cells in metabolically demanding tissues experience during nutrient deprivation. They found that extended starvation drives SIRT2, a NAD+-dependent deacetylase that typically resides in the cytoplasm and nucleus, to translocate into the mitochondria. This relocation matters because it places SIRT2 in the same compartment as ANT3, allowing the two proteins to bind directly. Once docked onto ANT3, SIRT2 performs its signature reaction: it removes an acetyl group from lysine 96, a specific residue on the ANT3 protein. Acetylation at lysine residues is a widespread post-translational modification that can alter a protein’s charge, structure, interactions, and stability, and the new work shows that the acetyl state of this one lysine carries enormous consequences for ANT3 behavior.

The consequences unfold along two parallel tracks. First, deacetylation of ANT3 at K96 promotes conformational changes in the protein, shifting it into a state that favors the formation of a complex with VDAC1, the voltage-dependent anion channel that sits in the outer mitochondrial membrane. The ANT3-VDAC1 pairing spans the contact sites between the inner and outer membranes and is considered a plausible architecture for the permeability transition pore, so enhancing this complex effectively assembles more of the death apparatus at the mitochondrial boundary. Second, and perhaps more surprisingly, deacetylated ANT3 binds more strongly to USP15, a deubiquitinating enzyme that removes ubiquitin tags from its substrates. Strengthened binding to USP15 enhances ANT3 deubiquitination, which stabilizes the ANT3 protein and raises its steady-state levels inside the mitochondria.

The logic of this dual mechanism is elegant and somewhat ruthless. By simultaneously reshaping ANT3 and protecting it from degradation, SIRT2 ensures that more of the transporter is present and more of it is locked into the pore-forming conformation with VDAC1. The result is an accelerated assembly of the permeability transition pore complex and, ultimately, an accelerated onset of cell death. In other words, starvation does not merely weaken the cell passively; it actively recruits a deacetylase to the mitochondria, which then stabilizes and reconfigures the very channel that will destroy the organelle. The study’s authors describe this as a rarely reported molecular mechanism in which SIRT2-mediated acetylation-dependent regulation governs programmed cell death.

Technically, the work illustrates how a single deacetylation event can be amplified into a systems-level outcome through feed-forward loops. The K96 deacetylation does not act alone; it recruits USP15, whose deubiquitinating activity further increases ANT3 abundance, which in turn increases the pool of ANT3 available to pair with VDAC1. This kind of positive feedback is characteristic of switch-like biological decisions, where a graded stress signal, in this case the duration of starvation, must be converted into a binary outcome: live or die. SIRT2’s dependence on NAD+ also ties the pathway directly to cellular metabolism, since NAD+ availability fluctuates with nutrient status and redox state. A starving cell, with its altered NAD+/NADH balance, thus provides both the signal and the enzymatic cofactor for the death-promoting modification.

The findings carry weight for a field that has struggled for decades with the molecular identity of the permeability transition pore. Genetic ablation of individual candidate components, including the ANT isoforms, has produced confusing and sometimes contradictory results, and the pore’s exact composition remains contested. By focusing on post-translational regulation rather than mere presence or absence of the protein, the new study offers a way to reconcile some of that ambiguity: ANT3 may be innocuous in one acetylation state and lethal in another. Conformational state, protein stability, and partner binding, all governed here by K96 acetylation, could explain why simply deleting a pore component does not always abolish permeability transition, since compensatory mechanisms and residual complexes may fill the gap.

There are also broader implications for human disease. Excessive mPTP opening is a hallmark of ischemia-reperfusion injury, where restored blood flow after a heart attack or stroke paradoxically kills cells that survived the initial insult, and it contributes to neurodegeneration, muscle wasting, and liver injury. Conversely, blocking pore opening can allow damaged cells to evade death, a trait exploited by some cancers. A pathway in which SIRT2, USP15, ANT3, and VDAC1 cooperate provides multiple potential intervention points. Small molecules that modulate SIRT2 activity are already under investigation in oncology and neurology, and deubiquitinase inhibitors are an active area of drug development. The Chongqing study does not test therapeutic compounds, but it maps the wiring that such compounds would need to respect.

The research, led by corresponding authors Liangbo Sun, Jiqin Lian, Mingzhen Yang, and Haojun Xiong, with Dong Liu, Meng He, and Jiahong Liu contributing equally as first authors, was supported by the National Natural Science Foundation of China and the Chongqing Natural Science Foundation. Animal experiments were conducted under the guidelines of the Army Medical University Laboratory Animal Center with ethics committee approval, and the authors declare no competing interests. The article was published open access on 29 September 2026, with raw western blotting data and supplementary materials made available alongside the paper, a transparency practice that allows independent researchers to scrutinize the key biochemical evidence.

What makes the study resonate beyond its immediate findings is the picture it paints of cellular death as an actively regulated, enzymatically driven process rather than a passive collapse. A starving cell does not merely run out of fuel; it deploys SIRT2 to the mitochondria, strips an acetyl group from ANT3 at lysine 96, stabilizes the protein through USP15-mediated deubiquitination, and assembles the ANT3-VDAC1 complex that breaches the mitochondrial barrier. Each step is reversible in principle, which means each step is a potential checkpoint at which the cell, or a clinician, could intervene. As researchers continue to dissect the permeability transition pore and the acetylation networks that tune it, the K96 switch on ANT3 stands out as a vivid example of how the smallest chemical changes can command the largest cellular decisions.

Subject of Research: SIRT2-mediated deacetylation of the mitochondrial protein ANT3 and its role in regulating programmed cell death during starvation

Article Title: SIRT2-mediated deacetylation of ANT3 at Lys96 promotes cell death

Article References: Liu, D., He, M., Liu, J., Shan, M., Ma, X., lu, L., Bi, X., Xiong, H., Yang, M., Lian, J., & Sun, L. (2026). SIRT2-mediated deacetylation of ANT3 at Lys96 promotes cell death. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03330-5

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03330-5

Keywords: SIRT2, ANT3, VDAC1, USP15, mitochondrial permeability transition pore, deacetylation, lysine 96, starvation, programmed cell death, deubiquitination, mitochondria, cell death discovery

The breadth of melatonin’s reported activities is striking. Beyond its sedative effect, the review catalogs antitumor, immunomodulatory, antioxidant, antihypertensive and cardioprotective actions, along with roles in regulating body weight, gastrointestinal function, reproduction and thermoregulation. Part of this versatility is chemical: melatonin crosses biological membranes freely and reaches nearly every compartment of the cell. Part of it is signaling: melatonin binds specific G-protein-coupled receptors, but it also engages intracellular pathways that govern whether a cell survives stress, divides, inflames or dies. The question the review tackles is which of these pathways best explains the hormone’s pharmacological reach, and its answer centers on SIRT1, the most intensively studied member of the mammalian sirtuin family.

SIRT1 is a nicotinamide adenine dinucleotide, or NAD+, dependent deacetylase, meaning it removes acetyl chemical groups from proteins only when the metabolic cofactor NAD+ is available. This makes the enzyme a direct sensor of cellular energy status, because NAD+ levels rise and fall with nutrient availability, fasting and metabolic strain. SIRT1 shuttles between the cytoplasm and the nucleus, where it strips acetyl groups from histones, the spools around which DNA is wound, and from a growing list of non-histone proteins including the tumor suppressor p53, the transcription factors FoxO and NF-κB, and the mitochondrial regulator PGC-1α. Through these targets, SIRT1 influences cell survival, metabolism, growth, aging and resistance to stress, which is precisely the portfolio of processes that goes wrong in chronic disease.

The review’s central claim is that melatonin can modulate SIRT1 activity, and that this modulation in turn shapes four fundamental cellular responses: inflammation, oxidative stress, apoptosis and autophagy. In inflammatory bowel disease, for example, recent work cited in the review shows that melatonin restores the intestinal mucosal barrier by activating a SIRT1-LKB1-pAMPK signaling axis. In autoimmune and sepsis models, SIRT1 deacetylates components of the NF-κB pathway and the NLRP3 inflammasome, damping the production of tumor necrosis factor alpha, interleukin-1 and other inflammatory mediators. Because NF-κB sits upstream of cyclooxygenase-2 and inducible nitric oxide synthase, a single deacetylation event can cascade into a broad suppression of the inflammatory program.

The cardiovascular evidence is among the most developed. In type 2 diabetic rats, reduced SIRT1 signaling worsens myocardial ischemia-reperfusion injury, and melatonin treatment restores protection through the enzyme. Melatonin receptor-mediated cardioprotection against ischemia-reperfusion has likewise been traced to SIRT1. In diabetic hearts, melatonin prevents Drp1-mediated mitochondrial fission, the excessive fragmentation of mitochondria that starves cardiomyocytes of energy, via the SIRT1-PGC-1α pathway, and activation of the SIRT1-PGC-1α-SIRT3 cascade protects against mitochondrial dysfunction in isoproterenol-induced myocardial injury. The chemotherapy drug doxorubicin, notorious for causing heart damage, appears less toxic when melatonin activates the Sirt1/Nrf2 pathway, inhibiting oxidative stress, pyroptosis and apoptosis. In sepsis-induced cardiac dysfunction, melatonin acts through SIRT1 to regulate both apoptosis and autophagy, including SIRT1-mediated deacetylation of beclin-1 and of the transcription factor TFEB, which orchestrates lysosomal clearance of damaged material.

The kidney tells a parallel story. Melatonin attenuates acute kidney ischemia-reperfusion injury in diabetic rats by activating the SIRT1/Nrf2/HO-1 axis, a canonical antioxidant pathway in which Nrf2, once deacetylated and stabilized, switches on heme oxygenase-1 and other detoxifying genes. In diabetic kidney disease, protection runs through SIRT1/NLRP3 signaling, curbing the inflammasome-driven inflammation that scars the filtering units of the kidney. Melatonin also prevents acute kidney injury in severely burned rats via SIRT1 activation, and in cadmium-induced proximal tubular injury it preserves mitochondrial function by blocking fission through SIRT1-PGC-1α. Perhaps most intriguingly, melatonin lowers the abundance of hypoxia-inducible factor 1α in human proximal tubular cells by preventing its deacetylation by sirtuin 1, a reminder that SIRT1’s effects are not uniformly protective but context-dependent, and that melatonin’s modulation of the enzyme can push it in either direction depending on the tissue and insult.

In the liver, the review highlights melatonin’s effects on non-alcoholic fatty liver disease, a condition now affecting a substantial share of the world’s overweight and obese population. Melatonin’s benefits in fatty liver models are linked to the microRNA-34a-5p/Sirt1 axis and to autophagy, the cellular recycling system that clears lipid droplets and damaged organelles. In hypercholesterolemic mice, melatonin’s modulation of sirtuin-1 attenuates liver injury. The enzyme also mediates protection against toxic exposures: melatonin inhibits benzo(a)pyrene-induced apoptosis in mouse liver through the miR-34a/Sirt1/autophagy pathway, and it attenuates arsenic-induced liver injury through Nrf2/HO-1, apoptosis and miR-34a/Sirt1/autophagy routes. In alcoholic liver injury, melatonin-induced SIRT1 disrupts the cereblon-YY1-CYP2E1 signaling pathway, reducing the oxidative metabolism of alcohol that generates damaging free radicals, while in sepsis-induced liver injury melatonin activates SIRT1/STAT3 signaling to rescue dysregulated gluconeogenesis.

The reproductive findings may prove the most clinically provocative. In polycystic ovary syndrome, melatonin enhances SIRT1 expression in granulosa cells to ameliorate excessive PINK1/Parkin-mediated mitophagy and to protect mitochondrial membranes through PDK1/Akt signaling, and it attenuates Drp1-driven mitochondrial fission through SIRT1 upregulation. The ROS/SIRT1/STAR axis has been identified as a target through which melatonin corrects atrazine-induced mitochondrial dysfunction and steroid disorders in granulosa cells. In oocytes, melatonin protects against chronic stress-induced meiotic defects by regulating SIRT1, and follicular fluid insufficiency of melatonin has been proposed as a reversible cause of the chromosomal abnormalities seen in oocytes of advanced maternal age. On the male side, melatonin protects mouse testes from palmitic acid-induced lipotoxicity in a SIRT1-dependent manner, ameliorates diabetic impairment of Leydig cell steroidogenic function through SIRT1 activation, and modulates SIRT1 to counter LPS-induced testicular nitro-oxidative stress and inflammation. Human trials add a translational note: melatonin supplementation improved semen parameters in men with idiopathic infertility in a triple-blind randomized placebo-controlled trial, and melatonin therapy added benefit to varicocelectomy in a double-blind trial, with epigenetic effects in a varicocele rat model mediated by silent information regulator 1.

The musculoskeletal section rounds out the picture. In osteoarthritis, melatonin exerts cytoprotective and anti-inflammatory effects in human chondrocyte cells and in rabbit models via the SIRT1 pathway, prevents cartilage matrix degradation by inhibiting NF-κB through SIRT1, and regulates chondrocyte hypertrophy and apoptosis through the Sirt1/P53/P21 axis. It also promotes sirtuin 1 expression to inhibit the IRE1α-XBP1S-CHOP branch of the unfolded protein response, reducing endoplasmic reticulum stress-mediated apoptosis in chondrocytes. In intervertebral disc degeneration, melatonin protects vertebral endplate chondrocytes against apoptosis and calcification via the Sirt1-autophagy pathway and holds promise through inhibiting M1-type macrophage polarization via SIRT1/Notch signaling. Even in cancer the relationship is bidirectional: whereas SIRT1 activation generally protects healthy tissue, melatonin’s antitumor activity in human osteosarcoma cells has been attributed to SIRT1 inhibition, underscoring that the same enzyme can be friend or foe depending on cellular context.

The authors are careful to note the limits of the evidence. Despite the breadth of preclinical data, they write that evidence regarding the role of SIRT1 in melatonin’s effects remains limited, and much of what is known comes from cell cultures and animal models rather than definitive human trials. Whether melatonin reliably activates SIRT1 in human tissues at supplement doses, and whether SIRT1 is necessary rather than merely correlated with the hormone’s benefits, will require pharmacological inhibitors, genetic models and properly powered clinical studies. Still, the synthesis is compelling in its coherence: a hormone produced by a tiny gland in the brain, acting through an NAD+-dependent enzyme that links metabolism to gene expression, appears to coordinate protective programs across organs as different as the heart, kidney, liver, ovary and joint. If future work confirms SIRT1 as the common mediator, melatonin’s humble reputation as a sleep aid may give way to something far more interesting, a cheap and safely tolerated molecule that tunes the body’s central longevity machinery.

Subject of Research: The role of the SIRT1 signaling pathway in the therapeutic effects of melatonin across disease models

Article Title: The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway

Article References: Vahidinia, Z., Behdarvandy, M., Azami Tameh, A., Barati, S., & Yasamian, A. (2026). The therapeutic potential of melatonin: Focus on the SIRT1 signaling pathway. Molecular Biology Reports, 53(1), Article 1667. https://doi.org/10.1007/s11033-026-12815-6

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12815-6

Keywords: melatonin, SIRT1, sirtuins, NAD+, deacetylation, oxidative stress, autophagy, apoptosis, cardioprotection, diabetic cardiomyopathy, non-alcoholic fatty liver disease, polycystic ovary syndrome

The starting material is deceptively ordinary. Aspergillus niger, the black mold long used to produce citric acid and enzymes at industrial scale, generates large quantities of spent mycelial biomass that is typically discarded or undervalued. Within its cell walls, however, lies a natural composite: chitin microfibrils entangled and covalently associated with glucan polysaccharides. This chitin–glucan architecture is, in effect, a prefabricated nanocomposite produced by biology itself. Unlike crustacean shell waste, which requires energy-intensive demineralization to remove calcium carbonate, fungal biomass is essentially mineral-free, giving it a favorable sustainability profile for chitin extraction. The Tianjin team cultivated A. niger in potato dextrose medium containing 12 grams per liter of potato extract and 60 grams per liter of glucose over 96 hours, producing a dense mycelial mat that served as the raw material for nanofiber fabrication.

The extraction strategy combines three sequential treatments. First, alkaline processing removes proteins and other soluble impurities from the cell wall matrix, enriching the insoluble chitin–glucan fraction. Second, a controlled partial deacetylation converts a proportion of the N-acetyl groups on the chitin backbone into free amine groups, generating chitosan-like character along the fiber surface. This chemical modification is critical: the newly exposed cationic amino groups are responsible for much of the material’s antibacterial behavior and improve its colloidal stability in water. Third, high-pressure homogenization subjects the chemically treated biomass to intense mechanical shear and cavitation forces that disentangle the cell wall architecture into individual nanofibers. The resulting partially deacetylated chitin–glucan complex nanofibers, or CGCNFs, have an average diameter of just 9.86 plus or minus 1.86 nanometers and an aspect ratio of approximately 25, meaning the fibers are slender ribbons a few dozen times longer than they are wide—an ideal geometry for reinforcing polymer films.

The economics of the process may prove as consequential as the science. Compared with conventional routes to chitin nanofibers, the proposed workflow achieved a 15 to 48 percent increase in nanofiber yield and reduced raw material costs by 75 to 81 percent. These gains stem partly from the choice of feedstock and partly from process integration, which avoids the harsh acid treatments and demineralization steps that inflate the cost and environmental footprint of crustacean-derived chitin. In a circular bioeconomy framework, spent microbial biomass from existing fermentation industries could feed directly into nanomaterial production, turning a disposal liability into a revenue stream. The authors position this as a sustainable strategy for biomass conversion and renewable polysaccharide fabrication, with the numbers to back up the claim.

Structural characterization confirmed that the treatment regimen did more than simply defibrillate the cell wall. Fourier-transform infrared spectroscopy, X-ray diffraction, and solid-state carbon-13 nuclear magnetic resonance spectroscopy collectively revealed enhanced surface functionalization of the nanofibers. The spectroscopic signatures showed increased exposure of amine groups alongside the preserved crystalline chitin core, a combination that underpins both the fibers’ reactivity and their mechanical integrity. Solid-state NMR, a technique particularly well suited to probing unlabeled fungal cell walls, allowed the researchers to track the chemical environment of the chitin and glucan carbons through each processing stage, verifying that partial deacetylation proceeded without destroying the glucan–chitin association that makes these fibers a natural composite rather than a mixture of separate polymers.

The most striking result is the antibacterial performance. The CGCNFs inhibited more than 99 percent of Escherichia coli, a Gram-negative bacterium, and Staphylococcus aureus, a Gram-positive pathogen. The mechanism is thought to follow the established antimicrobial behavior of chitosan-like polymers: the protonated amine groups on the fiber surfaces carry a positive charge at physiological pH, promoting electrostatic adhesion to the negatively charged bacterial cell envelope. In Gram-negative organisms this interaction disrupts the outer lipopolysaccharide membrane, while in Gram-positive species it interferes with the thick peptidoglycan layer and the cell membrane beneath, ultimately causing leakage of intracellular contents and loss of viability. Because the antimicrobial functionality is intrinsic to the biopolymer rather than added as a leachable additive, CGCNF-based materials could offer a durable and food-safe alternative to synthetic antimicrobial agents in packaging.

To demonstrate real-world utility, the team blended the nanofibers into polyvinyl alcohol, a water-soluble synthetic polymer widely used in films and coatings. The resulting CGCNF/PVA composite films displayed a tensile modulus of 4.2 gigapascals, a 162.5 percent increase relative to neat PVA films. This dramatic stiffening reflects classic nanocomposite reinforcement physics: rigid nanofibers dispersed at high aspect ratio form an interconnected network within the polymer matrix, efficiently transferring stress and restricting polymer chain mobility. The hydrogen-bonding compatibility between the hydroxyl-rich PVA and the hydroxyl- and amine-bearing surfaces of the nanofibers further strengthens the interface. The outcome is a multifunctional film that is simultaneously stronger, stiffer, and antibacterial—precisely the property combination sought for active food packaging that extends shelf life while resisting microbial spoilage.

The significance of the work extends beyond a single material system. Fungal sources of chitin have attracted growing attention as ecologically preferable alternatives to crustacean shells, with prior studies screening the sustainability and physicochemical properties of chitin and chitin–glucan across dozens of fungal species and assessing the environmental impact of nanofibril isolation from fungi compared with shrimp and crab shells. Previous efforts have produced fungal chitin nanopapers, heavy-metal-adsorbing filtration membranes, hemostatic hydrogels, and chitin nanofibers from mushroom extracts. The Tianjin study contributes a process-technology link that many of these works lacked: a route that is simultaneously high-yielding, low-cost, and compatible with industrially familiar unit operations such as alkaline extraction and high-pressure homogenization, applied to one of the most widely cultivated fungi in existence.

Challenges remain before fungal nanofibers reach commercial films and coatings. Scaling mycelium production and maintaining consistent cell wall composition across fermentation batches will demand tight bioprocess control, and the long-term migration behavior, biodegradation profile, and regulatory status of partially deacetylated chitin–glucan nanofibers in food-contact materials will need thorough evaluation. Nevertheless, the combination of a 9.86-nanometer fiber diameter, stronger-than-neat composite films, near-total bacterial inhibition, and an 81 percent reduction in raw material cost makes a compelling case that the next generation of antibacterial bioplastics may be grown, not drilled. As the biotechnology industry continues to generate mountains of spent fungal biomass, processes like this one suggest that the humble cell wall of Aspergillus niger may become one of the most valuable nanomaterial feedstocks of the coming decade.

Subject of Research: Extraction of antibacterial chitin–glucan nanofibers from Aspergillus niger fungal biomass for sustainable biopolymer films

Article Title: Extraction of nanochitin–glucan composite from Aspergillus niger with enhanced antibacterial activity

Article References: Ba, W., Che, M., Cui, M., Su, R., & Huang, R. (2026). Extraction of nanochitin–glucan composite from Aspergillus niger with enhanced antibacterial activity. Polymer Bulletin, 83(11), Article 637. https://doi.org/10.1007/s00289-026-06692-z

Image Credits: AI Generated

DOI: 10.1007/s00289-026-06692-z

Keywords: Aspergillus niger, chitin-glucan complex, nanofibers, antibacterial activity, fungal biomass, bioplastics, high-pressure homogenization, deacetylation, polyvinyl alcohol, food packaging, waste valorization, Polymers Bulletin