bims-celmim 2026-03-29 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2026–03–29
twenty papers selected by
Marc Segarra Mondejar, AINA

Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.
CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.
The pyruvate branch point controls lymphoid cancer cell dissemination.
Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.
Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?
Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models.
Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells.
Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.
Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.
Inorganic phosphate and the rapid mobilization of metabolic energy in neurons.
Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation.
A high-affinity split-HaloTag for live-cell protein labeling.
Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.
Mitochondria-Targeted Quinoline-Based Fluorescent Probes for Imaging of Viscosity and MAO‑A with High-Throughput Inhibitor Screening.
Mitochondrial lactate venting limits oxidative stress.
Mitochondrial NADP(H) integrates redox and metabolism.
Mitochondrial complex I in focus: mechanisms and therapeutic strategies of urinary system diseases.
Polyphosphate metabolism: Enzymatic pathways and regulation.
A deep learning pipeline for mapping in situ network-level neurovascular coupling in multi-photon fluorescence microscopy.
Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.

Nat Commun. 2026 Mar 24.

Mitochondrial metabolic imbalance drives diploidization in mouse haploid embryonic stem cells via NADPH overload.

Giulio Di Minin, Anna B Rüegg, Kevin Halter, Tobias Fuhrer, Tatjana Kleele, Nicola Zamboni, Anton Wutz.

A hallmark of mammals is a diploid genome. Despite constraints from dosage compensation and imprinting, haploid embryonic stem cells can be established. However, rapid diploidization is observed in such cultures from mice, rats, and humans, limiting their use and indicating counterselection of a haploid genome. Here, we use metabolic profiling to discover that diploidization is triggered by an imbalance that arises from a smaller cytoplasmic volume and increased mitochondrial density. Reduced respiration causes a change in redox potential, leading to increased NADPH. Conversely, we demonstrate that NADPH oxidation in the mitochondria is sufficient to stabilize the haploid genome. We further show that the redox change leads to reduced AURORA kinase activation on chromosomes, connecting metabolic state to mitotic regulation. Our data, therefore, identify a mitochondrial metabolic imbalance as the root cause of diploidization and connect redox dysregulation to karyotypic instability.

DOI: https://doi.org/10.1038/s41467-026-70939-6
Redox Biol. 2026 Mar 19. pii: S2213-2317(26)00130-8. [Epub ahead of print]92 104132

CTPS1 modulates mitophagy to propel diffuse large B-cell lymphoma via reshaping CEPT1-mediated phospholipid metabolism.

Chunyu Shang, Kaixin Du, Yixin Zou, Yixuan Han, Yuanli Gong, Ziwen Duan, Yifan Wu, Li Wang, Jianyong Li, Rui Gao, Wei Xu, Jinhua Liang.

  Despite effective first-line regimens, some patients with diffuse large B-cell lymphoma (DLBCL) still experience relapse or resistance, emphasizing the urgent need for innovative treatment approaches. Cytidine triphosphate synthase 1 (CTPS1) is a key regulatory and rate-limiting enzyme for de novo nucleotide synthesis pathway. However, the role of CTPS1 in DLBCL and its potential therapeutic value remain unknown. We found that high levels of CTPS1 were associated with poor prognosis in patients with DLBCL. The single-cell RNA sequencing (scRNA-seq) revealed that phospholipid metabolism and mitophagy-related pathways were activated in DLBCL cells with high CTPS1 expression. Mechanistically, CTPS1 up-regulated the expression of choline/ethanolamine phosphotransferase 1 (CEPT1) by increasing CTP availability, thereby reprogramming glycerophospholipid metabolism. The glycerophospholipids synthesized by CEPT1 maintained mitochondrial homeostasis and promoted BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, ultimately driving the DLBCL progression. Moreover, highly selective CTPS1 inhibitor R80 could reduce the viability of DLBCL cells.

Keywords:  CEPT1; CTPS1; Diffuse large B-Cell lymphoma; Mitophagy; Phospholipid metabolism

DOI:  https://doi.org/10.1016/j.redox.2026.104132
bioRxiv. 2026 Mar 18. pii: 2026.03.16.712182. [Epub ahead of print]

The pyruvate branch point controls lymphoid cancer cell dissemination.

Hamidullah Khan, Steven John, Sushmita Roy, Mohd Farhan, Nguyet Minh Hoang, Patrick Buethe, Aman Prasad, Aman Nihal, David T Yang, Lixin Rui, Jing Fan, Stefan M Schieke.

Cancer cell dissemination critically determines clinical prognosis, yet metabolic dependencies and corresponding therapeutic targets during spread of lymphoid malignancies remain poorly understood. Here we show that the pyruvate branch point operates as a metabolic checkpoint for lymphoid cancer cell migration and disease dissemination through mitochondrial ROS (mROS)/HIF-1a signaling. Isolation of highly migratory mROS hi cells led us to identify selective metabolic requirements of malignant lymphocyte migration and disease dissemination. Highly migratory cells show a reprogrammed metabolic profile characterized by increased glucose uptake and reduced glucose-carbon entry into the TCA cycle. Reprogramming of the TCA cycle with downregulation of citrate synthase provide the mechanistic basis for decreased pyruvate oxidation leading to increased migration and disease dissemination through mROS/HIF-1a signaling. Our findings connect central carbon metabolism and migratory capacity of lymphoid cancer cells and identify the pyruvate branch point as a metabolic switch and potential therapeutic target in lymphoid cancer cell dissemination.

DOI: https://doi.org/10.64898/2026.03.16.712182
bioRxiv. 2026 Mar 04. pii: 2026.03.04.709625. [Epub ahead of print]

Stress-Encoded Mitochondrial Plasticity: ATF4 Control of Mega-Mitochondria and Nanotunnel Communication.

Amber Crabtree, Suraj Thapliyal, Mohd Mabood Khan, Edgar Garza Lopez, Andrea Marshall, Calixto Pablo Hernandez Perez, Oleg Kovtun, Jenny C Schafer, Dea Pulatani, Yuho Kim, Sepiso K Masenga, Annet Kirabo, Jeremiah Afolabi, Melanie McReynolds, Renata O Pereira, Prasanna Venkhatesh, Prasanna Katti, Brian Glancy, Antentor Hinton.

Mitochondrial structural plasticity is a critical adaptive response to cellular stress, yet the transcriptional networks governing the formation of specialized mitochondrial architectures remain poorly defined. Here, we identified and demonstrated that activating transcription factor 4 (ATF4), the master regulator of the integrated stress response, directly regulates mitochondrial morphological remodeling through a novel ATF4-NRF1/Nrf2-MFN2 signaling axis. Using serial block-face scanning electron microscopy and three-dimensional reconstruction in Drosophila flight muscle, primary myotubes, and human skeletal muscle, we show that overexpression of ATF4 promotes significant mitochondrial elongation, increased cristae concentration, enhanced mitochondrial-endoplasmic reticulum contact site (MERC) formation, and the initiation of Mitochondrial Nanotunnels. In contrast, loss of ATF4 results in mitochondrial fragmentation and impaired aerobic capacity. Chromatin immunoprecipitation sequencing reveals direct ATF4 binding at the promoters of the genes encoding NRF1 and Nrf2, which in turn regulate MFN2 expression. Small-molecule inhibition studies further establish that activation of this hierarchical pathway is both necessary and sufficient for stress-induced mitochondrial structural adaptation. Together, these findings position ATF4 as a master regulator of mitochondrial architectural plasticity, providing a direct mechanistic link between cellular stress signaling and organelle remodeling.

DOI: https://doi.org/10.64898/2026.03.04.709625
Trends Mol Med. 2026 Mar 24. pii: S1471-4914(26)00033-X. [Epub ahead of print]

Cancer mtDNA mutations: metabolic plasticity and therapeutic promise?

Ersong Shang, Omar Aftab, Abbienaya Dayanamby, Laura C Greaves.

  Mitochondria, once viewed mainly as cellular powerhouses, are now recognised as key regulators of cancer metabolism, redox balance, and immune interactions. While early models emphasised a switch to aerobic glycolysis, many tumours exhibit metabolic plasticity and retain oxidative phosphorylation capacity. Mitochondrial DNA (mtDNA) mutations are common across cancers, yet their roles in carcinogenesis and therapy response remain unclear. Emerging base-editing technologies now enable modelling of these mutations, allowing the exploration of their impact on tumourigenesis, which may differ depending on mutation type, heteroplasmy, and tissue origin. mtDNA alterations also shape immune responses within the tumour microenvironment and therefore may influence treatment sensitivity. This review integrates recent advances on mtDNA's role in cancer biology and explores therapeutic opportunities for targeting mitochondrial metabolism.

Keywords:  DNA, mitochondrial; genes, neoplasm; neoplasms; oxidative phosphorylation; tumour microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2026.02.003
Cell Rep Med. 2026 Mar 26. pii: S2666-3791(26)00124-2. [Epub ahead of print] 102707

Analysis of GRK2 aggregation in the pathology of Alzheimer disease in animal models.

Joshua Abd Alla, Alexander Perhal, Xuebin Fu, Andreas Langer, Yasser El Faramawy, Ursula Quitterer.

  The G-protein-coupled receptor kinase 2 (GRK2) exerts essential functions in cell growth and survival. Searching for a connection between GRK2 and the neurodegenerative Alzheimer disease (AD), we find increased aggregated serine-670-phosphorylated GRK2 (phospho-S670-GRK2) in brains of AD mice and patients with dementia likely due to AD. Harmful phospho-S670-GRK2 aggregation is induced by two hallmark proteins of AD: beta-amyloid and the neurofibrillary-tangle-inducing, TAU-P301L. Aggregated phospho-S670-GRK2 triggers aggregation of TOMM6 (translocase of outer mitochondrial membrane 6), promotes mitochondrial dysfunction, and enhances beta-amyloid. Transgenic expression of inactive GRK2-K220R or a GRK-inhibitory peptide proves that neuropathological features are caused by GRK2 inactivation. Restoration of TOMM6 by neuron-specific TOMM6 expression reduces beta-amyloid plaques but enhances soluble beta-amyloid and increases mortality. In contrast, reconstitution of monomeric GRK2 and proteasomal phospho-S670-GRK2 degradation by small molecules counteracts neuropathological AD features, prevents neuronal loss, and improves survival. Thus, targeting of pathological GRK2 aggregation slows aging-induced neurodegeneration.

Keywords:  ARRB1; Alzheimer disease; GRK2; TOMM6; molecular docking; proteasome; senescence

DOI:  https://doi.org/10.1016/j.xcrm.2026.102707
Oncogene. 2026 Mar 25.

Loss of ABCA3 disrupts lipid balance and leads to AMPK-dependent suppression of SREBP1 in glioblastoma stem cells.

Jun-Kyum Kim, Min Gi Park, Seok Won Ham, Seunghyun Yoon, Sua Kim, Junseok Jang, Hyejin Kim, Nayoung Hong, Jong Min Park, Cheol Gyu Park, Min Ji Park, Sang-Hun Choi, Jung Yun Kim, Hee-Young Jeon, Sunyoung Seo, Seon Yong Lee, Yeri Lee, Hee Jin Cho, Minseo Gwak, Eun-Jung Kim, Kiyoung Eun, Yong Jae Shin, Do-Hyun Nam, Se Hoon Kim, Seung Jun Yoo, Hyunggee Kim.

Malignant cancers exhibit distinct lipid metabolic features that support tumor initiation and progression. Glioblastoma (GBM) is an aggressive brain tumor driven by GBM stem cells (GSCs), which are responsible for tumor development and therapy resistance. However, effective treatments targeting vulnerable metabolic pathways in GSCs have not yet been developed. Here, we demonstrate that the ATP-binding cassette transporter A3 (ABCA3) maintains lipid metabolic balance in GSCs. ABCA3 is highly expressed in GSCs, where lipid biosynthesis is particularly active. Knocking down ABCA3 significantly reduces cell growth, self-renewal, viability, and tumor growth after intracranial implantation. These changes are caused by a profound disruption of lipid metabolic balance, as demonstrated by RNA sequencing and liquid chromatography-time-of-flight mass spectrometry, which revealed widespread alterations in lipid metabolism genes and lipid composition. Mechanistically, ABCA3 knockdown inhibits sterol regulatory element-binding protein 1 (SREBP1) signaling by accumulating acylcarnitines (ACs) caused by phospholipid breakdown. The increased ACs induce the production of mitochondrial reactive oxygen species, which activate adenosine monophosphate-activated protein kinase (AMPK), resulting in the inhibition of SREBP1 signaling and reduced GSC fitness. Overall, these findings suggest that ABCA3 maintains lipid metabolic balance in GSCs, and disrupting this function triggers AMPK-dependent suppression of SREBP1 signaling.

DOI: https://doi.org/10.1038/s41388-026-03736-6
Autophagy. 2026 Mar 22. 1-2

Diverse mitochondrial stresses activate PINK1-PRKN/parkin mitophagy by a unified mechanism.

Julia A Thayer, Derek P Narendra.

  Mutations in PINK1 and PRKN/parkin are the leading recessive causes of Parkinson disease (PD). Together PINK1 and PRKN form a mitophagy pathway for clearing damaged mitochondria from the cell. It was unclear, however, whether diverse forms of mitochondrial damage activate the PINK1-PRKN pathway through a unified mechanism. Recently, we demonstrated that loss of mitochondrial membrane potential (MMP) leads to the stabilization and activation of PINK1 under a wide range of mitochondrial stressors, including mitochondrial protein misfolding. Mechanistically, we suggest that the MMP is required at a key step of PINK1 import into mitochondria, in which PINK1 is transferred between the translocases of the outer and inner mitochondrial membranes. Consistent with this model, retention of active PINK1 of the outer membrane requires the translocase of the outer mitochondrial membrane (TOMM) complex, whereas import of PINK1 from the outer to inner membrane requires the TIMM23 (translocase of inner mitochondrial membrane 23) complex. Notably, chronic disruption of the TIMM23 complex is sufficient to stabilize active PINK1 in the TOMM complex, phenocopying MMP loss. Together, our findings suggest PINK1 primarily senses catastrophic drops in a mitochondrion's MMP: a dead-end for the mitochondrion's continued biogenesis.

Keywords:  Autophagy; PARK2; PARK6; mitochondria unfolded protein response; mitochondrial quality control

DOI:  https://doi.org/10.1080/15548627.2026.2646238
bioRxiv. 2026 Mar 18. pii: 2026.03.16.712209. [Epub ahead of print]

Chronic cold exposure induces plasticity of mitochondrial calcium uptake in beige and brown fat of UCP1-deficient mice.

Casandra G Chamorro, Sachin Pathuri, Rebeca Acin-Perez, Michael Chhan, Madeleine G Milner, Natalia Ermolova, Anthony E Jones, Ajit S Divakaruni, Linsey Stiles, Andrea L Hevener, Zhenqi Zhou, Orian S Shirihai, Yuriy Kirichok, Ambre M Bertholet.

Brown adipose tissue (BAT) is a unique tissue with mitochondria specialized for thermogenesis via the BAT-specific uncoupling protein 1 (UCP1). Ucp1 -/- mice cannot tolerate acute exposure to cold, illustrating the necessity of UCP1 for efficient mitochondrial thermogenesis. However, these mice adapt to low temperatures through a gradual acclimation process, suggesting a high degree of mitochondrial plasticity in brown and beige fat cells. This phenomenon, which remains to be fully elucidated, indicates the potential for these mitochondria to implement effective thermogenic mechanisms in the absence of uncoupling protein 1 (UCP1). Here, we investigated mitochondrial remodeling in beige and brown fat of Ucp1 -/- mice to determine how they fulfill their thermogenic role. Upon gradual acclimation to a cold environment, Ucp 1 -/- mice exhibited body metabolic parameters and temperatures in the interscapular region similar to those of wild-type mice of BAT, highlighting effective thermogenesis. Interestingly, mitochondrial patch-clamp analysis and a mitochondrial Ca 2+ swelling assay revealed a dramatic increase in Ca 2+ uptake depending on the mitochondrial calcium uniporter (MCU) in BAT mitochondria from Ucp1 -/- mice when robust thermogenesis was required. Mitochondrial remodeling was accompanied by markedly increased tethering between mitochondria and the endoplasmic reticulum (ER) in Ucp1 -/- mice, confirming a significant restructuring of the contact sites between the ER and mitochondria, likely to adapt to a new Ca 2+ homeostasis. Respiratory complexes also underwent significant reorganization, which partly led to a reduction in their assembly. Levels of ATP synthase and its F1 subcomplex increased, suggesting a major source of ATP consumption and energy expenditure. We propose a new role for MCU as a key regulator of mitochondrial plasticity, enabling efficient thermogenesis in beige and brown adipose tissues in the absence of UCP1.

DOI: https://doi.org/10.64898/2026.03.16.712209
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2602529123

Inorganic phosphate and the rapid mobilization of metabolic energy in neurons.

Paul C Rosen, Shivang Sullere, Panhui Fu, Juan R Martínez-François, Daniel J Brooks, Erica Kim, Chenghua Gu, Gary Yellen.

  Neurons experience brief, intense periods of energy demand when they are excited, but how they rapidly coordinate energy expenditure with production is incompletely understood. Part of the difficulty has been measuring the levels of molecules involved in this metabolic response with spatiotemporal precision in single live cells. Here, we engineered a quantitative fluorescent biosensor to monitor cytosolic inorganic phosphate (Pi), a fundamental component of energy metabolism that has a classically proposed but largely neglected role in activating glycolysis. Using two-photon fluorescence lifetime imaging, we observed millimolar increases in Pi within seconds of stimulating mouse neurons both ex vivo and in vivo. Drawing on results from metabolic modeling, biosensor imaging, and enzymology, we argue that Pi is a sensitive reporter of energy usage that potently links metabolic energy supply with demand in neurons. Quantitative live-cell imaging of Pi should be a valuable approach for studying bioenergetics more generally.

Keywords:  fluorescence lifetime imaging; fluorescent biosensors of metabolism; glycolytic regulation; neuronal energy metabolism

DOI:  https://doi.org/10.1073/pnas.2602529123
Cell Death Dis. 2026 Mar 24.

Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation.

Lijun Yang, Handi Sun, Ruonan Wang, Depeng Yang, Qi Gu, Guiping Zhao, Liping Sun, Xinghe Chen, Jianxin Lv, Xiaoyu Lin, Jiahui Cheng, Muhammad Luqman Akhtar, Mengmeng Zhang, Jingyu Zang, Xinyue Shi, Zihao Zhang, Lijun Deng, Lixing Xiao, Lei Yue, Wei Dong, Qinghua Jiang, Fang Han, Yu Li, Huan Nie.

Glutamine (Gln) metabolism serves dual metabolic roles: it fuels the tricarboxylic acid (TCA) cycle, while concurrently sustaining redox balance through glutathione (GSH) synthesis. γ-Glutamylcyclotransferase (GGCT), a key metabolic enzyme frequently overexpressed in various cancers, has an undefined role in directing glutamine metabolic flux during tumorigenesis. This study demonstrated that glutamine promotes cancer cell growth by regulating GSH and reactive oxygen species (ROS) levels, with this process being closely associated with GGCT expression. Knockdown of GGCT significantly inhibited tumor growth, depleted GSH, and elevated ROS levels, whereas overexpression of GGCT exerted the opposite effects. Furthermore, we refined and established the Gln/c-Myc/miR-29b-3p/GGCT regulatory axis. Notably, GGCT knockdown markedly altered mitochondrial morphology and impaired oxidative phosphorylation and glycolysis capacity. Targeted metabolomics analysis revealed that GGCT knockdown significantly reduced the abundance of TCA cycle intermediates, while GGCT overexpression substantially increased their levels. [U-13C]glutamine isotope tracing experiments showed that GGCT overexpression reduced Gln contribution to the TCA cycle and diverted it preferentially to the GSH synthesis pathway for ROS regulation. In contrast, [U-13C]glucose isotope tracing results demonstrated a significant increase in TCA cycle intermediates derived from glucose when GGCT was overexpressed. Additional, supplementation of sodium pyruvate and JX06 in GGCT-knockdown cells confirmed that this regulatory effect of GGCT-mediated changes in ROS was independent of energy metabolism pathways. Collectively, this study identifies GGCT as a metabolic switch that diverts Gln flux toward GSH synthesis to maintain redox homeostasis, while enhancing glucose-fueled anaplerosis into the TCA cycle to sustain cell proliferation. These findings highlight GGCT as a potential therapeutic target for disrupting cancer redox adaptation and metabolic plasticity.

DOI: https://doi.org/10.1038/s41419-026-08619-y
Nat Commun. 2026 Mar 25. pii: 2865. [Epub ahead of print]17(1):

A high-affinity split-HaloTag for live-cell protein labeling.

Yin-Hsi Lin, Julian Kompa, De-En Sun, Runyu Mao, Birgit Koch, Konstantin Hinnah, Jonas Wilhelm, Natascha Franz, Stefanie Kühn, Tanja Menche, Abdinasir Adow, Paula Breuer, Julien Hiblot, Kai Johnsson.

We introduce a high-affinity split-HaloTag comprised of a short peptide tag (Hpep, 14 residues) and a large, inactive fragment (cpHaloΔ3). Hpep binds to cpHaloΔ3 spontaneously with nanomolar affinity, enabling subsequent labeling with fluorescent HaloTag ligands. The small size of Hpep facilitates cloning-free endogenous protein tagging using CRISPR/Cas9 and the complementation of Hpep-tagged proteins can be achieved in live cells through co-expression with cpHaloΔ3 and in fixed cells through incubation with cpHaloΔ3. The approach is compatible with advanced microscopy techniques such as expansion microscopy and live-cell STED imaging. Additionally, variants of Hpep that modulate the spectral properties of labeled fluorophores enable simultaneous imaging of two different Hpep-tagged proteins via fluorescence lifetime microscopy. In summary, our high-affinity split-HaloTag is a robust and versatile tool for live-cell imaging and diverse applications in chemical biology.

DOI: https://doi.org/10.1038/s41467-026-71032-8
Elife. 2026 Mar 26. pii: e103118. [Epub ahead of print]15

Age-dependent H3K9 trimethylation by dSetdb1 impairs mitochondrial UPR leading to degeneration of olfactory neurons and loss of olfactory function in Drosophila.

Francisco Muñoz-Carvajal, Nicole Sanhueza, Mario Sanhueza, Felipe A Court.

  Aging is characterized by a decline in essential sensory functions, including olfaction, which is crucial for environmental interaction and survival. This decline is often paralleled by the cellular accumulation of dysfunctional mitochondria, particularly detrimental in post-mitotic cells such as neurons. Mitochondrial stress triggers the mitochondrial unfolded protein response (UPRMT), a pathway that activates mitochondrial chaperones and antioxidant enzymes. Critical to the efficacy of the UPRMT is the cellular chromatin state, influenced by the methylation of lysine 9 on histone 3 (H3K9). While it has been observed that the UPRMT response can diminish with an increase in H3K9 methylation, its direct impact on age-related neurodegenerative processes, especially in the context of olfactory function, has not been clearly established. Using Drosophila, we demonstrate that an age-dependent increase in H3K9 trimethylation by the methyltransferase dSetdb1 reduces the activation capacity of the UPRMT in olfactory projection neurons leading to neurodegeneration and loss of olfactory function. Age-related neuronal degeneration was associated with morphological alterations in mitochondria and an increase in reactive oxygen species levels. Importantly, forced demethylation of H3K9 through knockdown of dSetdb1 in olfactory projection neurons restored the UPRMT activation capacity in aged flies, and suppressed age-related mitochondrial morphological abnormalities. This in turn prevented age-associated neuronal degeneration and rescued age-dependent loss of olfactory function. Our findings highlight the effect of age-related epigenetic changes on the response capacity of the UPRMT, impacting neuronal integrity and function. Moreover, they suggest a potential therapeutic role for UPRMT regulators in age-related neurodegeneration and loss of olfactory function.

Keywords:  D. melanogaster; cell biology; neuroscience

DOI:  https://doi.org/10.7554/eLife.103118
Chem Biomed Imaging. 2026 Mar 23. 4(3): 422-430

Mitochondria-Targeted Quinoline-Based Fluorescent Probes for Imaging of Viscosity and MAO‑A with High-Throughput Inhibitor Screening.

Xiangjie Luo, Ling Li, Yu Zeng, Zheng Li, Mingyuan Sun, Yifan Zhong, Yong Qian.

  Monoamine oxidase A (MAO-A) is a key enzyme in neurotransmitter metabolism and oxidative stress regulation, while mitochondrial viscosity serves as an important indicator of organelle health. However, simultaneous detection of MAO-A activity and viscosity using a single fluorescent probe remains challenging. Here, we report a series of quinoline-based probes incorporating an N-alkylated tetrahydropyridine unit as an MAO-A-responsive moiety. Among them, CMTP-1 exhibited high viscosity sensitivity, generating a "turn-on" fluorescence response via restricted intramolecular rotation. Oxidation of the tetrahydropyridine by MAO-A produced a pyridinium group, triggering intramolecular charge transfer (ICT) and fluorescence quenching. CMTP-1 selectively localized to mitochondria, enabled visualization of endogenous MAO-A in neuroblastoma cells and zebrafish, and monitored viscosity changes in lipopolysaccharide (LPS)-induced inflammatory models. Furthermore, a CMTP-1-based high-throughput screening platform identified harmine as a potent MAO-A inhibitor. These results highlight CMTP-1 as a versatile tool for probing mitochondrial viscosity and MAO-A activity, with broad potential in biomedical research and drug discovery.

Keywords:  cell imaging; fluorescent probe; high throughput screening; monoamine oxidase A; viscosity

DOI:  https://doi.org/10.1021/cbmi.5c00132
Cell Metab. 2026 Mar 24. pii: S1550-4131(26)00093-8. [Epub ahead of print]

Mitochondrial lactate venting limits oxidative stress.

Daniela Rauseo, Yasna Contreras-Baeza, Mildreth Salazar, Abigail J Galarza, Sebastián Holtheuer-Gallardo, Hugo Faurand, Natali Cárcamo-Lemus, Raibel Suárez, Joel L Asenjo, Alexandra von Faber-Castell, Franco Silva, Valentina Mora-González, Jan Dernic, Luca Ravotto, Matthias T Wyss, Felipe Baeza-Lehnert, Iván Ruminot, Carlos Alvarez-Navarro, Alejandro San Martín, Bruno Weber, Pamela Y Sandoval, L Felipe Barros.

  Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix lactate dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and reactive oxygen species.

Keywords:  genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species

DOI:  https://doi.org/10.1016/j.cmet.2026.02.020
Trends Endocrinol Metab. 2026 Mar 25. pii: S1043-2760(25)00267-X. [Epub ahead of print]

Mitochondrial NADP(H) integrates redox and metabolism.

Ren Zhang, Kezhong Zhang.

  The compartmentalization of NAD(H) and NADP(H) is fundamental to cellular metabolism, enabling precise coordination of redox balance, biosynthetic reactions, and energy homeostasis. Within mitochondria, NADP(H) has long been viewed as a redox buffer supporting antioxidant defense and reductive biosynthesis. Emerging evidence, however, reveals that mitochondrial NADP(H) also drives oxidative metabolism and metabolic flexibility. Loss of the mitochondrial NAD kinase, which phosphorylates NAD(H) to generate mitochondrial NADP(H), disrupts NADP(H)-dependent pathways that sustain oxidative metabolism and systemic energy balance. These advances reposition mitochondrial NADP(H) as an integrative regulator that links redox homeostasis with energy metabolism across cellular and systemic levels, with broad implications for metabolic disease.

Keywords:  NAD(H); NADK2; NADP(H); fatty acid oxidation; mitochondria; redox

DOI:  https://doi.org/10.1016/j.tem.2025.12.003
Front Physiol. 2026 ;17 1753159

Mitochondrial complex I in focus: mechanisms and therapeutic strategies of urinary system diseases.

Fangqiu Yu, Yixuan Li, Ruonan Qu, Zhong Wang, Wenqiang An, Yan Chen, Zhongjin Yue, Wei Wang.

  Recent research findings on the role of mitochondrial complex I (CI) in promoting renal cell carcinoma metastasis have been published in Nature. Mitochondria, as essential intracellular organelles in mammalian cells, play a pivotal role in orchestrating biological oxidation processes and are crucial for maintaining cellular metabolic homeostasis. Severe mitochondrial dysfunction, particularly involving CI, can lead to the development of urinary system diseases by initiating a cascade of events such as inflammation, impaired mitochondrial autophagy, and related processes. This article explores the involvement of CI in the pathogenesis and progression of urinary system diseases. It begins by introducing fundamental theories related to CI research in urinary system diseases, including its evolution, structure, function, and role in cellular metabolism. The epidemiology of CI-associated urinary system diseases, encompassing both neoplastic and non-neoplastic conditions and their associated risk factors, is subsequently discussed. The article further elaborates on the pathological mechanisms, diagnostic techniques, and therapeutic strategies targeting CI in these diseases. In conclusion, this review addresses the controversies and future directions within this research domain, aiming to provide a comprehensive understanding of the CI in urinary system diseases. It also emphasizes potential avenues for future research and translational applications.

Keywords:  disease diagnosis; gene mutation; metabolism; mitochondrial complex I; therapies; urinary system diseases

DOI:  https://doi.org/10.3389/fphys.2026.1753159
Biochim Biophys Acta Mol Cell Res. 2026 Mar 19. pii: S0167-4889(26)00034-0. [Epub ahead of print]1873(4): 120138

Polyphosphate metabolism: Enzymatic pathways and regulation.

Sarah Krukenberg, Giuliano A Kullik, Thomas Renné.

  Polyphosphate (polyP) is an ancient, evolutionarily conserved inorganic polymer found in all domains of life. PolyP functions in energy storage, metal chelation, phosphate buffering, and regulation of fundamental physiological processes such as blood coagulation, bone mineralisation, and mitochondrial energy metabolism. Here, we summarize current knowledge of polyP-metabolizing enzymes. In prokaryotes, polyP synthesis is primarily catalysed by polyphosphate kinases (PPK1 and PPK2), which synthesize long-chain polymers from adenosine triphosphate (ATP) or guanosine triphosphate (GTP); notable these enzymes are absent in higher eukaryotes. In yeast, the vacuolar transporter chaperone (VTC) complex functions as a polyP polymerase-translocase, coupling synthesis with vacuolar import. In mammals, the enzymatic machinery responsible for polyP formation remains elusive, although mitochondrial F1F0-ATP synthase and inositol pyrophosphate signalling have been implicated. PolyP degradation is mediated by two major enzyme families: exo- and endopolyphosphatases. Members of these families - including exopolyphosphatases (PPX) and endopolyphosphatases (PPN) in yeast and bacteria as well as Nudix hydrolases and h-Prune in mammals - play key roles in maintaining intracellular phosphate homeostasis and regulating the dynamic turnover of polyP. Defining the molecular pathways of polyP synthesis and degradation will reveal novel therapeutic targets in infection, thrombosis, and metabolic disease.

Keywords:  biopolymer; endopolyphosphatases; evolution; exopolyphosphatases; h-prune; phosphate; polyphosphate; polyphosphate kinase; polyphosphate synthetase

DOI:  https://doi.org/10.1016/j.bbamcr.2026.120138
Elife. 2026 Mar 24. pii: RP95525. [Epub ahead of print]13

A deep learning pipeline for mapping in situ network-level neurovascular coupling in multi-photon fluorescence microscopy.

Matthew W Rozak, James R Mester, Ahmadreza Attarpour, Adrienne Dorr, Shruti Patel, Margaret Koletar, Mary E Hill, Joanne McLaurin, Maged Goubran, Bojana Stefanovic.

  Functional hyperemia is a well-established hallmark of healthy brain function, whereby local brain blood flow adjusts in response to a change in the activity of the surrounding neurons. Although functional hyperemia has been extensively studied at the level of both tissue and individual vessels, vascular network-level coordination remains largely unknown. To bridge this gap, we developed a deep learning-based pipeline that uses two-photon fluorescence microscopy images of cerebral microcirculation to enable automated reconstruction and quantification of the geometric changes across the microvascular network, comprising hundreds of interconnected blood vessels, pre and post-activation of the neighboring neurons. The pipeline's utility was demonstrated in the Thy1-ChR2 optogenetic mouse model, where we observed network-wide vessel radius changes to depend on the photostimulation intensity, with both dilations and constrictions occurring across the cortical depth, at an average of 16.1±14.3 μm (mean ± SD) away from the most proximal neuron for dilations; and at 21.9±14.6 μm away for constrictions. We observed a significant heterogeneity of the vascular radius changes within vessels, with radius adjustment varying by an average of 24 ± 28% of the resting diameter, likely reflecting the heterogeneity of the distribution of contractile cells on the vessel walls. A graph theory-based network analysis revealed that the assortativity of adjacent blood vessel responses rose by 152 ± 65% at 4.3 mW/mm2 of blue photostimulation vs. the control, with a 4% median increase in the efficiency of the capillary networks during this level of blue photostimulation in relation to the baseline. Interrogating individual vessels is thus not sufficient to predict how the blood flow is modulated in the network. Our pipeline, enables tracking of the microvascular network geometry over time, relating caliber adjustments to vessel wall-associated cells' state, and mapping network-level flow distribution impairments in experimental models of disease.

Keywords:  blood vessels; machine learning; mouse; neuroscience; neurovascular coupling; optogenetics; physics of living systems; rat

DOI:  https://doi.org/10.7554/eLife.95525
Cell Signal. 2026 Mar 23. pii: S0898-6568(26)00148-8. [Epub ahead of print]143 112496

Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.

Lujing Mao, Juan Zou, Huimin Jin, Wenyan Liao, Yukun Li, Daichao Wu.

  Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8+ T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8+ T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.

Keywords:  CD8(+) T cells; Ferroptosis; Immunotherapy; Lipid metabolism; T cell exhaustion; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellsig.2026.112496