bims-cesemi 2026-05-24 papers

Issue of 2026–05–24
six papers selected by
Julio Cesar Cardenas, Universidad Mayor

Mol Biol Rep. 2026 May 22. pii: 817. [Epub ahead of print]53(1):

DDRGK1 regulates muscle development by maintaining mitochondrial calcium homeostasis and oxidative phosphorylation via stabilizing IP3R.

Ping Li, Lingfei Li, Mali Guo, Junjie Xu, Yafei Cai.

BACKGROUND: Mitochondrial calcium homeostasis is essential for oxidative phosphorylation (OXPHOS) and cellular energy production. DDRGK1 is an ER‑localized adaptor protein, which is critical for maintaining ER homeostasis, protein stability, and organelle communication. However, the role of DDRGK1 in regulating mitochondrial function remains largely unknown. This study aims to define the role of DDRGK1 in mitochondrial calcium signaling and bioenergetics.
METHODS AND RESULTS: Through biochemical analyses in cellular models, we identify DDRGK1 as a direct interactor and stabilizer of IP3R, preventing its ubiquitin-mediated degradation. DDRGK1 deficiency reduces IP3R protein levels, impairing mitochondrial calcium uptake and OXPHOS activity, as assessed by respirometry and ATP measurements. Consequent bioenergetic deficits are accompanied by calcium overload-induced ER stress, which activates C/EBP-homologous protein (CHOP) and suppresses the PGC‑1α pathway, thereby inhibiting mitochondrial biogenesis.
CONCLUSIONS: The DDRGK1-IP3R axis constitutes a critical regulatory module in mitochondrial calcium signaling and energy metabolism. Disruption of this axis underlies bioenergetic failure and provides mechanistic insight into the pathogenesis of skeletal muscle metabolic disorders and related mitochondrial diseases.

Keywords: DDRGK1; ER-mitochondrial crosstalk; inositol 1,4,5-trisphosphate receptor; mitochondrial calcium homeostasis; oxidative phosphorylation

DOI: https://doi.org/10.1007/s11033-026-12009-0

EMBO J. 2026 May 22.

Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.

Pooja Jadiya, Elena Berezhnaya, Devin W Kolmetzky, Dhanendra Tomar, Henry M Cohen, Shatakshi Shukla, Manfred Thomas, Salman Khaledi, Joanne F Garbincius, Liam Kennedy, Oniel Salik, Darpan Raghav, Alycia N Hildebrand, John W Elrod.

Loss of mCa2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer's disease (AD) by promoting mitochondrial Ca2+ (mCa2+) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of mCa2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal mCa2+ uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca2+ content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu. These results suggest that inhibition of neuronal mCa2+ uptake represents a powerful therapeutic target to impede AD progression.

DOI: https://doi.org/10.1038/s44318-026-00809-w

Redox Biol. 2026 May 15. pii: S2213-2317(26)00211-9. [Epub ahead of print]94 104213

Nrf2 modulates cytosolic and mitochondrial calcium signal.

Alessandra Preziuso, Artyom Y Baev, Fozila R Rustamova, Sharadha Dayalan Naidu, Lauren Millichap, Plamena R Angelova, Vincenzo Lariccia, Albena T Dinkova-Kostova, Andrey Y Abramov.

Nrf2 is a transcription factor which regulates ∼1% of the mammalian genome and is responsible for orchestrating the cellular defense against oxidative, inflammatory and metabolic stress. Calcium (Ca2+) is a ubiquitous intracellular messenger which controls most cellular processes, from fertilization to cell death. Nrf2 and Ca2+ are involved in a large number of similar physiological processes, but it is not clear if they can regulate each other. Here, using primary co-cultures of neurons and astrocytes we asked if Nrf2 activation or deficiency alters physiological Ca2+ signaling and mitochondrial Ca2+ handling in brain cells. We found that activation of Nrf2 leads to an increase in the amplitude of Ca2+ peak and a faster Ca2+efflux in response to glutamate and ATP in neurons and astrocytes. Interestingly, Nrf2-deficient neurons and astrocytes also had higher Ca2+ peaks in response to glutamate and ATP, but the recovery in neurons was significantly delayed. Genetic (Keap1-knockdown) or pharmacological (ovameloxolone, RTA-408) activation of Nrf2 increases mitochondrial Ca2+ uptake and mitochondrial Ca2+ capacity, and this correlates with increased activity of the Na+/Ca2+/Li+ exchanger (NCLX) and inhibition of the mitochondrial permeability transition pore (mPTP). Conversely, mitochondria in neurons and astrocytes from Nrf2-knockout mice had a lower Ca2+ uptake, lower mitochondrial Ca2+ capacity and lower mitochondrial Ca2+efflux, making these cell vulnerable to Ca2+-induced cell death. Thus, Nrf2 modulates cytosolic calcium signaling and activates the mitochondrial NCLX, increasing the mitochondrial Ca2+ capacity, which adds another critical aspect to the multifaceted nature of Nrf2-mediated cytoprotection.

Keywords: Astrocyte; Calcium signal; Keap1; Mitochondria; Neuron; Nrf2

DOI: https://doi.org/10.1016/j.redox.2026.104213

Commun Biol. 2026 May 20.

Mitochondrial Ca2+ uniporter (MCU) variants form plasma-membrane channels.

Iuliia Polina, Jyotsna Mishra, Michael W Cypress, Maria Landherr, Nedyalka Valkov, Isabel Chaput, Bridget Nieto, Brian Rhee, Ameneh Ahrari, Nathan DeMichaelis, Kye-Im Jeon, Ulrike Mende, Peng Zhang, Bong Sook Jhun, Jin O-Uchi.

MCU, originally known as CCDC109A, is widely recognized as the gene responsible for encoding a pore-forming subunit of a Ca2+-selective channel, mitochondrial Ca2+ uniporter complex (mtCUC). While MCU expression is typically highly mitochondrial-specific, we report here a protein variant derived from the MCU gene, termed MCU-S, which lacks the mitochondria-targeting sequence (MTS) and forms a Ca2+-permeable channel outside of mitochondria. The mRNA of MCU-S was ubiquitously expressed in all cell types/tissues tested, with particularly high expression in human platelets. MCU-S protein formed Ca2+ channels at the plasma membrane, which exhibited similar channel properties to those observed in mtCUC. MCU-S channels at the plasma membrane served as an additional Ca2+ influx pathway for platelet activation. Our findings show that the MCU-S functions are completely distinct from the originally reported functions of the MCU gene and provide additional insights into the molecular importance of MCU variant-dependent cellular Ca2+ handling.

DOI: https://doi.org/10.1038/s42003-026-10285-x

PLoS One. 2026 ;21(5): e0348801

S-palmitoylation regulates the function of the mitochondria-associated endoplasmic reticulum membrane to alleviate the senescence of nucleus pulposus cells.

Qi Liang, Jianfeng Zhang, Jingchuan Yan, Weidong Guo, Jian Zhao, Li Lin, Shuang Li, Daxiong Feng, Bo Liao.

Intervertebral disc degeneration (IVDD) is the primary cause of spinal degenerative diseases. Nucleus pulposus (NP) cell senescence is a significant pathological manifestation of IVDD. Here, we constructed a hypoxia-induced NP cell model to clarify the mechanisms by which S-palmitoylation is involved in NPC senescence. The IP3R S-palmitoylation of NP cells was significantly reduced under hypoxic conditions, contributing to abnormalities in mitochondria-associated membranes (MAMs). The study found that cellular expression of Bax, Bcl-2, Cleaved-Caspase8, Cleaved-Caspase3, MMP3, and MMP13 was promoted, while COL2 and AGG expression was inhibited. The up-regulated palmitoylation-modifying enzyme DHHC6 can promote IP3R S-palmitoylation modification and regulate GRP75, VDAC1, Drp1, and Mfn2 expression. It can inhibit apoptosis in NP cells, reduce intracellular calcium and ROS levels, elevate mitochondrial membrane potential, and reduce γ-H2AX expression levels. It also inhibited the protein expression levels of hypoxia-induced apoptosis molecules, matrix-degrading enzymes, and up-regulated extracellular matrix protein expression. These results suggested that hypoxia-induced IP3R depalmitoylation might play a role in structural and functional abnormalities in MAMs, which trigger senescence in NP cells.

DOI: https://doi.org/10.1371/journal.pone.0348801

Nature. 2026 May 20.

Mitochondrial L-2-hydroxyglutarate is a physiological signalling metabolite.

L-2-Hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH) oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to L-2-HG accumulation and causes L-2-hydroxyglutaric aciduria2. Thus, L-2-HG is often classified as a toxic metabolite2-5. However, whether L-2-HG has any physiological function is unclear. Here we investigate whether L-2-HG qualifies as a physiological signalling metabolite by testing three criteria: regulated levels, defined molecular targets and a measurable physiological function. We report that an increase in mitochondrial NADH/NAD+ ratio drives malate dehydrogenase 2 (MDH2) to reduce 2-OG into L-2-HG. Moreover, L2HGDH oxidizes L-2-HG back to 2-OG in the mitochondrial matrix without requiring a functional electron transport chain. Through proteome integral solubility alteration assays, we show that the KDM4 family of H3K9 demethylases are L-2-HG-responsive targets. L-2-HG represses the nascent transcription of specific genes in mouse embryonic stem cells and increases H3K9me3 (a repressive histone mark) at these loci. In vivo, early embryonic L2HGDH overexpression in mice systemically reduces L-2-HG levels, impairs postnatal growth, causes mortality and produces selective functional and histological renal vulnerabilities. In postnatal kidneys, this reduction in L-2-HG causes H3K9me3 loss at L1MdTf retrotransposons and their derepression, which coincides with the activation of the integrated stress response and inflammation pathways. Our findings establish mitochondrial L-2-HG as a physiological signalling metabolite and indicate that metabolites previously regarded as toxic may also have crucial physiological functions.

DOI: https://doi.org/10.1038/s41586-026-10564-x