bims-miptne 2026-09-06 papers

bims-miptne

Biomed News

on Mitochondrial permeability transition pore-dependent necrosis

Issue of 2026–09–06
nine papers selected by
Oluwatobi Samuel Adegbite, University of Liverpool

Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.
Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.
Reframing neuropsychiatric disorders: Nuclear calcium signaling as a core signaling axis of mitochondrial proteostasis and synaptic energy homeostasis.
Mitophagy: a regulator and therapeutic target in cerebral ischemia/reperfusion injury.
Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.
Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.
A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.
ORAI Ca2+ channels and STIM1 drive capillary-to-arteriole communication in neurovascular coupling.
Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.

J Neurosci. 2026 Sep 03. pii: e0515262026. [Epub ahead of print]

Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity.

Dobromila Pekala, Maurice Safar, Madeline Lampert, Duc Doung, Stephanie Zlatic, Victor Faundez, Peter Wenner.

Neural function is maintained through homeostatic mechanisms that are engaged following perturbations to the nervous system. Homeostatic plasticity is thought to be critical for establishing and stabilizing appropriate levels of network function. Neurons are proposed to detect deviations in activity through intracellular calcium signaling, such that changes in calcium levels initiate compensatory mechanisms that restore activity and calcium to baseline. This sensing process is generally assumed to occur in the cytoplasm, however, recent work suggests that it may reside inside mitochondria. We test this in the chick embryo (either sex) spinal cord. We show that perturbations known to induce homeostatic plasticity preferentially alter the mitochondrial proteome, including components of the tricarboxylic acid (TCA) cycle, a pathway sensitive to calcium entry into mitochondria. We then tested whether calcium influx into the mitochondrial matrix contributes to the induction of homeostatic plasticity in motoneurons. Pharmacological blockade of the mitochondrial calcium uniporter (MCU), which mediates calcium entry into the matrix, produced a robust and sustained increase in spontaneous network activity (SNA). Using Ru265 to inhibit MCU function, we confirmed a reduction in mitochondrial calcium, while cytoplasmic calcium levels were largely unchanged or slightly elevated. MCU blockade was accompanied by an increase in excitatory synaptic strength consistent with homeostatic synaptic plasticity. The underlying mechanisms overlapped with those previously described in this preparation following activity or neurotransmitter blockade. Together, these findings support a model in which mitochondria contribute to the initiation of homeostatic synaptic plasticity, potentially by sensing changes in calcium transients within the mitochondrial matrix.Significance Statement Homeostatic plasticity is thought to play a critical role in maintaining circuit function. Although substantial progress has been made in identifying the mechanisms underlying the expression of homeostatic plasticity, the upstream triggers remain poorly understood. Cytoplasmic calcium has been proposed as a key signal in the detection of perturbations in neural circuit activity and in initiating compensatory responses. Here, we present findings consistent with the idea that the sensor for network activity and homeostatic synaptic plasticity tracks mitochondrial calcium. Identifying the sensor that initiates homeostatic mechanisms will be essential for understanding the functional objectives of this form of plasticity and may provide a foundation for pharmacologically targeting this pathway in conditions characterized by altered network activity.

DOI: https://doi.org/10.1523/JNEUROSCI.0515-26.2026
Cell Death Differ. 2026 Sep 03.

Direct binding of the C-terminal sequences of Bim and Bak contributes to efficient Bak activation.

Dang Nguyen, Sabina Trebinjac, Tobias B Beigl, Frank Essmann, Kathryn M Murphy, David W Andrews.

Apoptosis is regulated by Bcl-2 family of proteins through direct binding interactions at the mitochondrial outer membrane. Bak, a key cellular executioner protein in this family, differs from the other executioner proteins Bax and Bok in that it is constitutively localized at the mitochondrial outer membrane via its C-terminal sequence (CTS). Binding of the BH3-only protein Bim triggers conformational changes in Bak that lead to oligomerization and mitochondrial membrane permeabilization. However, the molecular mechanism by which Bim activates Bak remains incompletely understood. Here we demonstrate both in vitro and in cells, that efficient Bim-mediated activation of Bak requires not only the binding of the BH3-motif of Bim to the canonical BH3-binding groove of Bak, but also sequence specific, direct binding of the Bim-CTS to the Bak-CTS. These findings reveal an unexpected contribution of the Bak-CTS to the molecular control of Bak activation during apoptosis.

DOI: https://doi.org/10.1038/s41418-026-01848-w
Mol Cell Neurosci. 2026 Aug 30. pii: S1044-7431(26)00044-8. [Epub ahead of print] 104114

Reframing neuropsychiatric disorders: Nuclear calcium signaling as a core signaling axis of mitochondrial proteostasis and synaptic energy homeostasis.

Maneesh Mohan, Ashi Mannan, Debasmita Mondal, Charu Chabara, Sanya Aneja, Vetriselvan Subramaniyan, Thakur Gurjeet Singh.

  Neuropsychiatric disorders have a high global health impact; however, the molecular basis of these disorders is still not fully understood due to the intricate complexity of neuronal homeostasis. In this review article, we have highlighted an emerging paradigm that places nuclear calcium signaling at the apex of cellular metabolism by bridging synaptic functions and mitochondrial proteostasis. We have highlighted how cytosolic and nucleoplasmic Ca2+ transients orchestrate a "transcription-to-translation" process that is crucial for the expression of mitochondrial proteasomal and biogenesis-related genes. In this review article, we have critically analyzed pathways, including ER-IP3R coupling, MCU-mediated Ca2+ uptake, and the PINK1-Parkin pathway, that contribute to a "synaptic energy gap" due to bioenergetic failure and oxidative stress arising from aberrant calcium homeostasis. One of the major highlights of this review article is our critical examination of the CaMKII-CREB-BDNF pathway, which plays a crucial role in mitochondrial biogenesis in response to alterations in energy homeostasis. We have explored beyond the conventional by critically analyzing how modern psychotropic agents such as Ketamine, Lithium, and Valproate effectively reboot these pathways to overcome bioenergetic failure. Through the integration of the latest advances in structural biology with clinical psychiatry, this review creates a framework where mitochondrial pathology is not only a consequence, but rather a cause, of psychiatric disorders. Ultimately, this review creates a framework for developing next-generation, molecularly targeted therapeutics capable of healing the energetic defects that underlie the human mind.

Keywords:  Mitochondrial proteostasis; Neuropsychiatric bioenergetics; Nuclear calcium signaling; Synaptic energy gap; Transcription-to-translation coupling

DOI:  https://doi.org/10.1016/j.mcn.2026.104114
Mitochondrion. 2026 Sep 04. pii: S1567-7249(26)00102-9. [Epub ahead of print] 102212

Mitophagy: a regulator and therapeutic target in cerebral ischemia/reperfusion injury.

Chalton Manengu, Zhen Tian, Huifeng Zhu.

  Cerebral ischemia/reperfusion (I/R) injury refers to the exacerbation of tissue damage following the restoration of blood flow to ischemic brain regions. This condition remains a major challenge in the clinical management of ischemic stroke due to limited therapeutic options. At present, no approved drugs specifically target cerebral I/R injury. Multiple mechanisms contribute to its pathogenesis, with mitochondrial dysfunction playing a central role. During cerebral I/R injury, mitochondria generate excessive reactive oxygen species (ROS), leading to impaired mitochondrial function and further tissue damage. In addition, mitochondrial calcium overload triggers neuronal apoptosis, which promotes disease progression. Given the critical role of mitochondrial dysfunction, preservation of mitochondrial homeostasis may attenuate cerebral I/R injury. Mitophagy, a selective process that removes damaged mitochondria, has been shown to mitigate cerebral I/R injury by limiting the release of harmful mitochondrial-derived factors. Therefore, mitophagy represents a potential therapeutic target for maintaining mitochondrial homeostasis in cerebral I/R injury treatment. This review summarizes the molecular regulation of mitophagy, its role in cerebral I/R injury, and current therapeutic strategies aimed at modulating mitophagy.

Keywords:  Cerebral I/R injury; Mitochondrial dysfunction; Mitophagy; Neurological diseases

DOI:  https://doi.org/10.1016/j.mito.2026.102212
Sci Adv. 2026 Sep 04. 12(36): eaef8132

Mitochondrial superoxide-induced mitohormesis is mediated by citrate and cardioprotective.

Matthew P Donnelly, Kailash Chandra Mangalhara, Yuening Liu, Kathryn Lande, Gladys R Rojas, Kym J Grae, Mack B Reynolds, Sagnika Ghosh, Neva Olliffe, Pau B Esparza-Moltó, Melissa A Johnson, Suzanne Dufresne, Allison Y Louie, Alexandra G Moyzis, Deann Guan, Åsa B Gustafsson, Christina G Towers, Pallav Kosuri, Christian M Metallo, Diana C Hargreaves, Gerald S Shadel.

Mitohormesis, whereby transient mitochondrial stress induces adaptive signaling, promotes organismal resilience and longevity in invertebrates, but how this operates in mammals and the underlying metabolic signals involved remain unclear. Using a mouse model of mitohormesis, we show that transient mitochondrial superoxide stress during embryogenesis reprograms the adult heart to enhance mitochondrial biogenesis and antioxidant capacity. These adaptations confer protection against mitochondrial and oxidative injury in models of doxorubicin-induced cardiotoxicity, preserving mitochondrial content and preventing cardiac dysfunction and remodeling. Using a cell model of superoxide-mediated mitohormesis, we find that inhibition of mitochondrial aconitase promotes citrate export to the cytosol, where its conversion to acetyl-coenzyme A drives histone acetylation and mitohormetic protection from oxidative stress. Preventing mitochondrial citrate export abolishes these adaptations, while Aco2 silencing or citrate supplementation recapitulates the response. Together, our findings identify mitochondrial citrate as a redox-sensitive second messenger linking mitochondrial superoxide stress to durable epigenetic and mitohormetic remodeling.

DOI: https://doi.org/10.1126/sciadv.aef8132
Elife. 2026 Sep 02. pii: RP106976. [Epub ahead of print]14

Cardiolipin deficiency disrupts electron transport chain and drives steatohepatitis.

Marisa J Brothwell, Guoshen Cao, J Alan Maschek, Annelise M Poss, Alek D Peterlin, Liping Wang, Talia B Baker, Justin L Shahtout, Piyarat Siripoksup, Quentinn J Pearce, Jordan M Johnson, Fabian M Finger, Alexandre Prola, Sarah A Pellizzari, Gillian L Hale, Allison M Manuel, Shinya Watanabe, Edwin R Miranda, Kajsa E Affolter, Trevor S Tippetts, Linda S Nikolova, Ran Hee Choi, Stephen T Decker, Mallikarjun Patil, J Leon Catrow, William L Holland, Sara M Nowinski, Daniel S Lark, Kelsey H Fisher-Wellman, Patrice N Mimche, Kimberley Evason, James E Cox, Scott A Summers, Zach Gerhart-Hines, Katsuhiko Funai.

  Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to metabolic dysfunction-associated steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, mitochondrial cardiolipin (CL) was downregulated with MASLD/MASH in humans and in mice. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous and robust MASH with extensive steatotic and fibrotic phenotype. Loss of CL paradoxically increased mitochondrial respiratory capacity but also promoted electron leak primarily at sites IIIQO and IIF of the electron transport chain (ETC), reduced the formation of I + III2 + IV respiratory supercomplex, and disrupted the propensity of coenzyme Q to become reduced. Thus, low mitochondrial CL disrupts the ETC to promote oxidative stress and contributes to the pathogenesis of MASH.

Keywords:  cardiolipin; cell biology; human; liver; mitochondria; mouse

DOI:  https://doi.org/10.7554/eLife.106976
Nat Commun. 2026 Jul 30. pii: 9473. [Epub ahead of print]17(1):

A GABARAP-PtdIns3K-C1 positive feedback loop at the heart of the phagophore nucleation.

Antoine N Dessus, Yohei Ohashi, Maxime Bourguet, Tomos E Morgan, Anastasia Nunez, Maria Manifava, Nicholas T Ktistakis, Roger L Williams.

In mammalian cells, autophagosomes can reach diameters of over 1000 nm within 30 min after triggering starvation, but how such substantial amounts of membranes can be synthesized remains elusive. The phagophore initiation needs the lipid kinase PIK3C3-Complex 1 (PtdIns3K-C1), which produces phosphatidylinositol-3-phosphate (PtdIns3P). PtdIns3P recruits WIPI2 that facilitates lipidation of mammalian ATG8 (mATG8) family proteins on phagophores. Here we show that recombinant membrane-coupled GABARAP binds to and potently activates PtdIns3K-C1. By a combination of cryo-electron microscopy, structural mass spectrometry, activity assays and mutagenesis, we show that GABARAP activates PtdIns3K-C1 through two binding sites. We propose that once GABARAP is indirectly recruited by PtdIns3P generated by basal activity of PtdIns3K-C1, a positive feedback loop is formed where PtdIns3K-C1 interacts with GABARAP and becomes activated to produce more PtdIns3P, thereby further stimulating GABARAP lipidation. This mechanism would be central for autophagosome biogenesis, where enlarged membranes need to be rapidly synthesized.

DOI: https://doi.org/10.1038/s41467-026-76135-w
Sci Signal. 2026 Sep;19(953): eaef0939

ORAI Ca2+ channels and STIM1 drive capillary-to-arteriole communication in neurovascular coupling.

Boris Lavanderos, Alfredo Sanchez-Solano, Wanchun Zhu, Pratish Thakore, Evan Yamasaki, Yilin Chen, Yumei Feng Earley, Mohamed Trebak, Scott Earley.

Neurovascular coupling (NVC), which is initiated by the brain's dense capillary network, matches blood flow to neuronal activity. We found that ORAI1 channels and their regulator STIM1, the main drivers of store-operated Ca2+ entry, were essential for communication from capillaries, which detect neuronal metabolic need, to upstream arterioles, which dilate to increase regional flow. Endothelial cell-specific knockout of either Stim1 or Orai1 disrupted capillary Ca2+ signals, impaired sustained capillary-driven arteriole dilation, and reduced increases in blood flow in the somatosensory cortex evoked by whisker stimulation, indicating that ORAI1 and STIM1 sustain cerebral blood flow during prolonged neuronal stimulation. Moreover, mice with endothelial cell-specific deficiency of Stim1 or Orai1 showed cognitive impairment, whereas mice with endothelial cell-specific deficiency of Orai3 showed anxiety-like behaviors. These in vivo results link impaired capillary-to-arteriole signaling to isoform-specific behavioral aberrations. These findings demonstrate that intravascular communication mediated by ORAI channels and STIM1 is fundamental for NVC and brain health.

DOI: https://doi.org/10.1126/scisignal.aef0939
Nat Neurosci. 2026 Sep 02.

Mitochondrial calcium influx-driven bioenergetics selectively enable drug addiction.

Jun Gao, Haixin Zhao, Xiao Han, Lingmin Zeng, Jingqi Pan, Guangqin Liu, Xuechen Wei, Changwei Liu, Wenjun Wu, Siqi Chen, Jiayi Chen, Ting Li, Jiye Yin, Tao Zhou, Xue-Min Zhang, Ai-Ling Li, Teng Li, Xin Pan.

Addictive substances hijack the brain's reward system, driving pathological dopamine surges that underlie compulsive behavior and addiction. However, directly targeting dopamine signaling for treatment risks disrupting natural reward processes. Here we identify a bioenergetic mechanism that selectively promotes addiction-related dopamine release and behaviors. Opioids and methamphetamine, but not natural rewards, induce mitochondrial calcium (Ca2+) influx via the mitochondrial calcium uniporter (MCU) in dopaminergic terminals of the nucleus accumbens. Optogenetic stimulation reveals that this mitochondrial Ca2+ influx occurs exclusively during high-intensity dopaminergic neuronal activation. This Ca2+ influx drives rapid ATP production, compensating for energy deficits caused by neuronal hyperactivity and enabling sustained dopamine release. Genetic deletion or pharmacological inhibition of MCU in dopaminergic neurons selectively reduces drug-induced dopamine release and prevents addictive behaviors while sparing natural reward processing. These findings uncover a distinct mitochondrial bioenergetic mechanism underlying drug reward and propose MCU as a therapeutic target for addiction treatment.

DOI: https://doi.org/10.1038/s41593-026-02421-x