bims-miptne 2025-05-18 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2025–05–18
ten papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance.
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment.
Resveratrol's Pro-Apoptotic Effects in Cancer Are Mediated Through the Interaction and Oligomerization of the Mitochondrial VDAC1.
Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.
Novel Mitochondria-Targeted NIR Cyanine Cy750M-C1 Nanoparticles for Chemotherapy against Triple-Negative Breast Cancer.
MTHFD2: A significant mitochondrial metabolic enzyme and a novel target for anticancer therapy.
Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α.
Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.
The mitophagy receptors BNIP3 and NIX mediate tight attachment and expansion of the isolation membrane to mitochondria.

Int Immunopharmacol. 2025 May 12. pii: S1567-5769(25)00853-7. [Epub ahead of print]158 114863

Mitochondrial calcium overload contributes to mechanical allodynia in neuropathic pain via inducing mitochondrial dynamic imbalance.

Dan-Yang Li, Lin Liu, Dai-Qiang Liu, Long-Qing Zhang, Ya-Qun Zhou, Wei Mei.

  Neuropathic pain is a chronic and devastating clinical problem with few effective treatments. Mitochondrial dysfunction plays a critical role in the pathological process of neuropathic pain. Recently, mitochondrial calcium overload has been identified as the initial part of mitochondrial dysfunction, such as dynamic imbalance and excessive superoxide. Mitochondrial Ca2+ uniporter (MCU) serves as the primary channel for mitochondrial Ca2+ uptake, and Na+/Ca2+ exchanger (NCLX) is the dominant mechanism for mitochondrial calcium ion excretion. Herein, we investigated the role of mitochondrial calcium overload and its regulated channels in a rat model of neuropathic pain. Our results showed significant mitochondrial calcium overload in the spinal dorsal horn of SNI rats, accompanied by the upregulation of MCU and downregulation of NCLX. MCU inhibition or NCLX overexpression remarkably relieved mechanical allodynia and mitochondrial high calcium levels in SNI rats. Conversely, upregulation of MCU or downregulation of NCLX induced mitochondrial calcium overload and mechanical allodynia in naïve rats. We also observed excessive mitochondrial fission and reduced fusion in the spinal cord of SNI rats, which could be mitigated by MCU inhibition and NCLX overexpression, respectively. Notably, mitochondrial fission inhibitor or mitochondrial fusion promoter effectively reversed the MCU overexpression or NCLX knockdown-induced mechanical allodynia. Collectively, our data indicate that the MCU/NCLX-mediated mitochondrial calcium overload drives excessive mitochondrial fission, which promotes the progression of SNI.

Keywords:  Mitochondrial calcium overload; Mitochondrial dynamic; Neuropathic pain

DOI:  https://doi.org/10.1016/j.intimp.2025.114863
Nat Cell Biol. 2025 May;27(5): 847-862

ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.

Che-Chia Hsu, Chi-Yun Wang, Rajesh Kumar Manne, Zhen Cai, Vasudevarao Penugurti, Rajni Kant, Ling Bai, Bo-Syong Pan, Tingjin Chen, Yuan-Ru Chen, Hsin-En Wu, Yan Jin, Haiwei Gu, Chia-Yang Li, Hui-Kuan Lin.

MPC1 and MPC2 are two well-known components of the mitochondrial pyruvate carrier (MPC) complex maintaining MPC activity to transport pyruvate into mitochondria for tricarboxylic acid (TCA) cycle entry in mammalian cells. It is currently unknown whether there is an additional MPC component crucially maintaining MPC complex activity for pyruvate mitochondrial import. Here we show that ALDH4A1, a proline-metabolizing enzyme localized in mitochondria, serves as a previously unrecognized MPC component maintaining pyruvate mitochondrial import and the TCA cycle independently of its enzymatic activity. Loss of ALDH4A1 in mammalian cells impairs pyruvate entry to mitochondria, resulting in defective TCA cycle entry. ALDH4A1 forms an active trimeric complex with MPC1-MPC2 to maintain the integrity and oligomerization of MPC1-MPC2 and facilitates pyruvate transport in an in vitro system. ALDH4A1 displays tumour suppression by maintaining MPC complex activity. Our study identifies ALDH4A1 as an essential component of MPC for pyruvate mitochondrial import, TCA cycle entry and tumour suppression.

DOI: https://doi.org/10.1038/s41556-025-01651-8
Int J Mol Sci. 2025 May 05. pii: 4379. [Epub ahead of print]26(9):

Rescue of the First Mitochondrial Membrane Carrier, the mPiC, by TAT-Mediated Protein Replacement Treatment.

Samar Zabit, Orly Melloul, Michal Lichtenstein, Erin L Seifert, Haya Lorberboum-Galski.

  The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (Pi) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca2+ uptake and buffering of matrix Ca2+. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first year of life. We have developed a novel therapeutic approach using TAT-mPiC fusion protein for cellular delivery since the TAT peptide enables delivery of proteins across biological membranes. We designed, produced, and purified the TAT-mPiC fusion protein. The fusion protein is delivered into the mitochondria and localizes within the mIM, its natural cellular location, as a processed protein. Treatment of mPiC-knockdown cells with TAT-mPiC fusion protein increased cell growth and improved bioenergetic capabilities, as measured by oxygen consumption rate (OCR), ATP production, and reduction in lactate secretion. Most importantly, TAT-mPiC restored Pi and Cu delivery into the mitochondrial matrix. TAT-mPiC fusion protein also restored the mitochondrial activity of cells harboring various mitochondrial defects. This study presents the first successful delivery of a mitochondrial transmembrane carrier using the TAT-fusion system, offering a potential early treatment strategy for newborns with mPiC deficiency.

Keywords:  TAT-mediated therapy; mitochondria; mitochondrial phosphate carrier; mitochondrial phosphate carrier deficiency (MPCD); protein replacement treatment

DOI:  https://doi.org/10.3390/ijms26094379
Int J Mol Sci. 2025 Apr 22. pii: 3963. [Epub ahead of print]26(9):

Resveratrol's Pro-Apoptotic Effects in Cancer Are Mediated Through the Interaction and Oligomerization of the Mitochondrial VDAC1.

Tal Raviv, Anna Shteinfer-Kuzmine, Meital M Moyal, Varda Shoshan-Barmatz.

  Resveratrol is a naturally occurring phenolic compound found in various foods such as red wine, chocolate, peanuts, and blueberries. Both in-vitro and in-vivo studies have shown that it has a broad spectrum of pharmacological effects such as providing cellular protection and promoting longevity. These effects include antioxidant, anti-inflammatory, neuroprotective, and anti-viral properties, as well as improvements in cardio-metabolic health and anti-aging benefits. Additionally, resveratrol has demonstrated the ability to induce cell death and inhibit tumor growth across different types and stages of cancer. However, the dual effects of resveratrol-acting to support cell survival in some contexts, while inducing cell death in others-is still not fully understood. In this study, we identify a novel target for resveratrol: the voltage-dependent anion channel 1 (VDAC1), a multi-functional outer mitochondrial membrane protein that plays a key role in regulating both cell survival and death. Our findings show that resveratrol increased VDAC1 expression levels and promoted its oligomerization, leading to apoptotic cell death. Additionally, resveratrol elevated intracellular Ca2+ levels and enhanced the production of reactive oxygen species (ROS). Resveratrol also induced the detachment of hexokinase I from VDAC1, a key enzyme in metabolism, and regulating apoptosis. When VDAC1 expression was silenced using specific siRNA, resveratrol-induced cell death was significantly reduced, indicating that VDAC1 is essential for its pro-apoptotic effects. Additionally, both resveratrol and its analog, trans-2,3,5,4'-tetrahydroxystilbene-2-O-glucoside (TSG), directly interacted with purified VDAC1, as revealed by microscale thermophoresis, with similar binding affinities. However, unlike resveratrol, TSG did not induce VDAC1 overexpression or apoptosis. These results demonstrate that resveratrol-induced apoptosis is linked to increased VDAC1 expression and its oligomerization. This positions resveratrol not only as a protective agent, but also as a pro-apoptotic compound. Consequently, resveratrol offers a promising therapeutic approach for cancer, with potentially fewer side effects compared to conventional treatments, due to its natural origins in plants and food products.

Keywords:  VDAC1; apoptosis; hexokinase; mitochondria; resveratrol

DOI:  https://doi.org/10.3390/ijms26093963
Front Immunol. 2025 ;16 1572927

Mitochondrial metabolism is rapidly re-activated in mature neutrophils to support stimulation-induced response.

Jorgo Lika, James A Votava, Rupsa Datta, Carlos A Mellado Fritz, Aleksandr M Kralovec, Frances M Smith, Anna Huttenlocher, Melissa C Skala, Jing Fan.

   Introduction: Neutrophils are highly abundant innate immune cells that are constantly produced from myeloid progenitors in the bone marrow. Differentiated neutrophils can perform an arsenal of effector functions critical for host defense. This study aims to quantitatively understand neutrophil mitochondrial metabolism throughout differentiation and activation, and to elucidate the impact of mitochondrial metabolism on neutrophil functions.
Methods: To study metabolic remodeling throughout neutrophil differentiation, murine ER-Hoxb8 myeloid progenitor-derived neutrophils and human induced pluripotent stem cell-derived neutrophils were assessed as models. To study the metabolic remodeling upon neutrophil activation, differentiated ER-Hoxb8 neutrophils and primary human neutrophils were activated with various stimuli, including ionomycin, monosodium urate crystals, and phorbol 12-myristate 13-acetate. Characterization of cellular metabolism by isotopic tracing, extracellular flux analysis, metabolomics, and fluorescence-lifetime imaging microscopy revealed dynamic changes in mitochondrial metabolism.
Results: As neutrophils mature, mitochondrial metabolism decreases drastically, energy production is offloaded from oxidative phosphorylation, and glucose oxidation through the TCA cycle is substantially reduced. Nonetheless, mature neutrophils retain the capacity for mitochondrial metabolism. Upon stimulation with certain stimuli, TCA cycle is rapidly activated. Mitochondrial pyruvate carrier inhibitors reduce this re-activation of the TCA cycle and inhibit the release of neutrophil extracellular traps. Treatment with these inhibitors also impacts neutrophil redox status, migration, and apoptosis without significantly changing overall bioenergetics.
Conclusions: Together, these results demonstrate that mitochondrial metabolism is dynamically remodeled and plays a significant role in neutrophils. Furthermore, these findings point to the therapeutic potential of mitochondrial pyruvate carrier inhibitors in a range of conditions where dysregulated neutrophil response drives inflammation and contributes to pathology.

Keywords:  TCA cycle; metabolism; mitochondria; neutrophil; neutrophil extracellular traps

DOI:  https://doi.org/10.3389/fimmu.2025.1572927
ACS Biomater Sci Eng. 2025 May 13.

Novel Mitochondria-Targeted NIR Cyanine Cy750M-C1 Nanoparticles for Chemotherapy against Triple-Negative Breast Cancer.

Zhilin Shen, Fenglin Zhang, Jiawang Yang, Kaihang Zhang, Feng Liang, Han Mu, Li Shi, Jijun Jiang, Yuanzhi Yang, Zhixuan Lin, Jie Gao, Ning Gao.

  Mitochondrial metabolism plays an important role in promoting cancer development, making mitochondria a novel promising target for cancer therapy. Current mitochondria-targeted fluorescent agents can specifically accumulate in the mitochondria of cancer cells and can be applied for cancer imaging and therapy. However, their clinical application is still limited due to the poor solubility and lower tumor-specific distribution. In the present study, we synthesized a novel NIR small-molecule dye, Cy750M-C1, and evaluated its optical properties, mitochondrial distribution, and anticancer activity. We also synthesized nanoparticles loading Cy750M-C1 (Cy750M-C1-FA-NPs) and demonstrated that Cy750M-C1-FA-NPs are specifically targeted to the tumor and dramatically inhibited tumor growth in vivo. The mechanistic study revealed that Cy750M-C1 specifically targeted mitochondria of TNBC cells, subsequently promoting ROS production through inhibition of mitochondrial complexes (complexes I, III, and IV) and OXPHOS and depletion of ATP, leading, in turn, to AMPK activation and Drp1 dephosphorylation mediating the mitochondrial translocation of Drp1 and BAX and ultimately inducing mitochondrial fission, caspase activation, as well as apoptosis. Overall, our data implicate that Cy750M-C1 could be developed as a novel anticancer agent with mitochondria-targeting ability and NIR fluorescence imaging and that Cy750M-C1-FA-NPs could also be considered as promising drug delivery carriers for antitumor agents.

Keywords:  NIR cyanine; chemotherapy; mitochondria; nanoparticles; triple-negative breast cancer; tumor targeting

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00343
Drug Discov Today. 2025 May 08. pii: S1359-6446(25)00085-6. [Epub ahead of print] 104372

MTHFD2: A significant mitochondrial metabolic enzyme and a novel target for anticancer therapy.

Shuyu Liu, Xiaoke Wang, Liye Zhao, Liangren Zhang, Yali Song.

  Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a crucial mitochondrial enzyme that operates within the folate one-carbon metabolic pathway. In recent years, it has been discovered that its expression is upregulated in numerous tumors and is correlated with the onset and progression of tumors, as well as poor prognosis. In contrast to its isoenzymes, it is overexpressed in tumors and is either expressed at low levels or not expressed at all in normal tissues. Consequently, it has received extensive attention and has been proposed as a novel anticancer target. In this paper, we review the functions of MTHFD2 in tumors, its regulatory mechanisms, and research progress on MTHFD2 inhibitors. Additionally, we provide insights into future research directions and the design and development of inhibitors for MTHFD2.

Keywords:  MTHFD2; anticancer; inhibitors

DOI:  https://doi.org/10.1016/j.drudis.2025.104372
FEBS J. 2025 May 13.

Metformin protects the heart against chronic intermittent hypoxia through AMPK-dependent phosphorylation of HIF-1α.

Sophie Moulin, Britanny Blachot-Minassian, Anita Kneppers, Amandine Thomas, Stéphanie Paradis, Laurent Bultot, Claire Arnaud, Jean-Louis Pépin, Luc Bertrand, Rémi Mounier, Elise Belaidi.

  Chronic intermittent hypoxia (IH), a major feature of obstructive sleep apnea syndrome (OSA), is associated with greater severity of myocardial infarction. In this study, we performed RNA sequencing of cardiac samples from mice exposed to IH, which reveals a specific transcriptomic signature of the disease, relative to mitochondrial remodeling and cell death. Corresponding to its activation under chronic IH, we stabilized the Hypoxia Inducible Factor-1α (HIF-1α) in cardiac cells in vitro and observed its association with an increased autophagic flux. In accordance, IH induced autophagy and mitophagy, which are decreased in HIF-1α+/- mice compared to wild-type animals, suggesting that HIF-1 plays a significant role in IH-induced mitochondrial remodeling. Next, we showed that the AMPK metabolic sensor, typically activated by mitochondrial stress, is inhibited after 3 weeks of IH in hearts. Therefore, we assessed the effect of metformin, an anti-diabetic drug and potent activator of AMPK, on myocardial response to ischemia-reperfusion (I/R) injury. Daily administration of metformin significantly decreases infarct size without any systemic beneficial effect on insulin resistance under IH conditions. The cardioprotective effect of metformin was lost in AMPKα2 knock-out mice, demonstrating that AMPKα2 isoform promotes metformin-induced cardioprotection in mice exposed to IH. Mechanistically, we found that metformin inhibits IH-induced mitophagy in myocardium and decreases HIF-1α nuclear expression in mice subjected to IH. In vitro experiments demonstrated that metformin induced HIF-1α phosphorylation, decreased its nuclear localization, and HIF-1 transcriptional activity. Collectively, these results identify the AMPKα2 metabolic sensor as a novel modulator of HIF-1 activity. Our data suggest that metformin could be considered as a cardioprotective drug in OSA patients independently of their metabolic status.

Keywords:  AMPK; HIF‐1; intermittent hypoxia; ischemia–reperfusion; myocardium

DOI:  https://doi.org/10.1111/febs.70110
Proc Natl Acad Sci U S A. 2025 May 20. 122(20): e2426179122

Estrogen-related receptors regulate innate and adaptive muscle mitochondrial energetics through cooperative and distinct actions.

Weiwei Fan, Tae Gyu Oh, Hui J Wang, Lillian Crossley, Mingxiao He, Hunter Robbins, Chandra Koopari, Yang Dai, Morgan L Truitt, Christopher Liddle, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.

  Mitochondrial energy metabolism is vital for muscle function and is tightly controlled at the transcriptional level, both in the basal state and during adaptive muscle remodeling. The importance of the transcription factors estrogen-related receptors (ERRs) in controlling innate mitochondrial energetics has been recently demonstrated. However, whether different ERR isoforms display distinct functions in glycolytic versus oxidative myofibers is largely unknown. Moreover, their roles in regulating exercise-induced adaptive mitochondrial biogenesis remain unclear. Using muscle-specific single and combinatorial knockout mouse models, we have identified both cooperative and distinct roles of the ERR isoforms ERRα and ERRγ in regulating mitochondrial energy metabolism in different muscles. We demonstrate the essential roles of both these ERRs in mediating adaptive mitochondrial biogenesis in response to exercise training. We further show that PGC1α-induced mitochondrial biogenesis is completely abolished in primary myotubes with ERRα deletion but not ERRγ, highlighting distinct roles of these two isoforms in adaptive mitochondrial remodeling. Mechanistically, we find that both ERRs directly bind to the majority of mitochondrial energetic genes and control their expression, largely through collaborative binding to the same genomic loci. Collectively, our findings reveal critical and direct regulatory roles of ERRα and ERRγ in governing both innate and adaptive mitochondrial energetics in skeletal muscle.

Keywords:  PGC1; energy metabolism; estrogen-related receptor; mitochondria; muscle

DOI:  https://doi.org/10.1073/pnas.2426179122
J Cell Biol. 2025 Jul 07. pii: e202408166. [Epub ahead of print]224(7):

The mitophagy receptors BNIP3 and NIX mediate tight attachment and expansion of the isolation membrane to mitochondria.

Shun-Ichi Yamashita, Ritsuko Arai, Hiroshi Hada, Benjamin Scott Padman, Michael Lazarou, David C Chan, Tomotake Kanki, Satoshi Waguri.

BNIP3 and NIX are the main receptors for mitophagy, but their mechanisms of action remain elusive. Here, we used correlative light EM (CLEM) and electron tomography to reveal the tight attachment of isolation membranes (IMs) to mitochondrial protrusions, often connected with ER via thin tubular and/or linear structures. In BNIP3/NIX-double knockout (DKO) HeLa cells, the ULK1 complex and nascent IM formed on mitochondria, but the IM did not expand. Artificial tethering of LC3B to mitochondria induced mitophagy that was equally efficient in DKO cells and WT cells. BNIP3 and NIX accumulated at the segregated mitochondrial protrusions via binding with LC3 through their LIR motifs but did not require dimer formation. Finally, the average distance between the IM and the mitochondrial surface in receptor-mediated mitophagy was significantly smaller than that in ubiquitin-mediated mitophagy. Collectively, these results indicate that BNIP3 and NIX are required for the tight attachment and expansion of the IM along the mitochondrial surface during mitophagy.

DOI: https://doi.org/10.1083/jcb.202408166