ArticleDiabetologia2016
Disruption of calcium transfer from ER to mitochondria links alterations of mitochondria-associated ER membrane integrity to hepatic insulin resistance.
Article in Diabetologia, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 89 papers.
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Who cites it
89 citing papers in PubMed, 160 citations in OpenAlex.
- Mitochondria‑endoplasmic reticulum contact site nexus: Molecular integration, disease pathogenesis and therapeutic opportunities (Review).International journal of molecular medicine · 2026Review
- GRP75 chaperone-driven mitochondria-ER membrane coupling promotes CaThe Journal of biological chemistry · 2026Article
- The spatiotemporal dynamics of MAMs: mechanisms, pathologies, and therapeutic rewiring.Cellular & molecular biology letters · 2026Review
- The MCU-MECOM Axis Orchestrates Glioblastoma Progression by Remodeling Mitochondrial Dynamics and Quality Control via MAMs.International journal of biological sciences · 2026Article
- Long-chain saturated free fatty acids induce pancreatic β-cell lipotoxic stress via HFrontiers in endocrinology · 2026Article
- The organelle oxidative-inflammatory network in polycystic ovary syndrome: from subcellular intercellular cascades to systemic comorbidities.Frontiers in immunology · 2026Review
- Spatial-Bioenergetic-Immune Axis in Type 2 Diabetes Mellitus-Associated Sarcopenia: A Review from Pathogenesis to Targeted Reconstruction.Journal of inflammation research · 2026Review
- Mitochondria-associated membranes (MAMs): molecular organization, cellular functions, and their role in health and disease.FEBS open bio · 2026Review
- The role of mitochondrial-associated endoplasmic reticulum membranes (MAMs) in diabetic microvascular complications: a review.Cell death & disease · 2025Review
- Acetylation of the Mitochondrial Chaperone GRP75 Governs ER-Mitochondrial Calcium Homeostasis and Hepatocyte Insulin Resistance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- Inducible skeletal muscle-specific p53 deletion alleviates high-fat diet-induced insulin resistance by modulating mitochondria-associated membrane in obese mice.Redox biology · 2025Article
- N-acetyl-phenylalanine induces hepatic steatosis in MASLD by disrupting ER-mitochondria calcium coupling and mitochondrial lipid oxidation.bioRxiv : the preprint server for biology · 2025Article
- Mitochondrial Calcium Uniporter Regulates Metabolic Remodeling and Smooth Muscle Cell Proliferation in Type 2 Diabetes.Journal of the American Heart Association · 2025Article
- Review
- Connecting the Dots: Mitochondrial Dysfunction, PCOS, and Insulin Resistance-Insights and Therapeutic Advances.International journal of molecular sciences · 2025Review
- Stbd1 stimulates AMPK signaling and alleviates insulin resistance in an in vitro hepatocyte model.The FEBS journal · 2025Article
- Cardiomyocyte-specific long noncoding RNA Trdn-as induces mitochondrial calcium overload by promoting the mFrontiers of medicine · 2025Article
- High-Fat Diet and Altered Radiation Response.Biology · 2025Review
- Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum CaACS pharmacology & translational science · 2025Article
29 more citing papers are in PubMed but not listed here.
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Authors and funding
20 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisMitochondria-associated endoplasmic reticulum membranes (MAMs) are regions of the endoplasmic reticulum (ER) tethered to mitochondria and controlling calcium (Ca(2+)) transfer between both organelles through the complex formed between the voltage-dependent anion channel, glucose-regulated protein 75 and inositol 1,4,5-triphosphate receptor (IP3R). We recently identified cyclophilin D (CYPD) as a new partner of this complex and demonstrated a new role for MAMs in the control of insulin's action in the liver. Here, we report on the mechanisms by which disruption of MAM integrity induces hepatic insulin resistance in CypD (also known as Ppif)-knockout (KO) mice.
methodsWe used either in vitro pharmacological and genetic inhibition of CYPD in HuH7 cells or in vivo loss of CYPD in mice to investigate ER-mitochondria interactions, inter-organelle Ca(2+) exchange, organelle homeostasis and insulin action.
resultsPharmacological and genetic inhibition of CYPD concomitantly reduced ER-mitochondria interactions, inhibited inter-organelle Ca(2+) exchange, induced ER stress and altered insulin signalling in HuH7 cells. In addition, histamine-stimulated Ca(2+) transfer from ER to mitochondria was blunted in isolated hepatocytes of CypD-KO mice and this was associated with an increase in ER calcium store. Interestingly, disruption of inter-organelle Ca(2+) transfer was associated with ER stress, mitochondrial dysfunction, lipid accumulation, activation of c-Jun N-terminal kinase (JNK) and protein kinase C (PKC)ε and insulin resistance in liver of CypD-KO mice. Finally, CYPD-related alterations of insulin signalling were mediated by activation of PKCε rather than JNK in HuH7 cells. CONCLUSIONS/
interpretationDisruption of IP3R-mediated Ca(2+) signalling in the liver of CypD-KO mice leads to hepatic insulin resistance through disruption of organelle interaction and function, increase in lipid accumulation and activation of PKCε. Modulation of ER-mitochondria Ca(2+) exchange may thus provide an exciting new avenue for treating hepatic insulin resistance.
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