TRPM7-mediated calcium signaling contributes to Hyperglycemia-induced mitochondrial dysfunction and apoptosis in retinal Muller cells

Cell Signal. 2026 Jul 7:112728. doi: 10.1016/j.cellsig.2026.112728. Online ahead of print.

ABSTRACT

Calcium signaling dysregulation is a critical trigger of mitochondrial dysfunction in metabolic disorders, yet the upstream mechanisms linking hyperglycemic stress to organellar Ca²⁺ overload remain poorly defined. The transient receptor potential melastatin 7 (TRPM7) channel functions as a Ca²⁺-permeable signaling node with unique kinase activity, but its role in hyperglycemia-induced glial injury is unknown. Here, we investigated whether TRPM7 mediates mitochondrial dysfunction and apoptosis in retinal Müller cells under hyperglycemic stress. Using a streptozotocin/high-fat diet-induced diabetic mouse model and high glucose-exposed Müller cells, we assessed retinal pathology, cell death, mitochondrial function, and intracellular Ca²⁺ dynamics. TRPM7 was genetically silenced via lentiviral shRNA to establish causality. In vivo, hyperglycemia induced retinal damage, oxidative stress, Müller cell activation, and apoptosis, accompanied by TRPM7 upregulation, although histological quantification was performed on a limited subset of animals (n = 3 mice/group). In vitro, high glucose triggered time-dependent TRPM7 upregulation, leading to sustained Ca²⁺ elevation, increased expression of voltage-dependent anion channel 1 (VDAC1), opening of the mitochondrial permeability transition pore (mPTP), collapse of mitochondrial membrane potential, ATP depletion, oxidative stress, and inflammatory activation. Genetic silencing of TRPM7 abrogated Ca²⁺ overload, downregulated VDAC1, restored mitochondrial integrity, suppressed oxidative stress and inflammation, and prevented apoptosis. These findings identify TRPM7 as a critical upstream signaling molecule that contributes to hyperglycemia-induced mitochondrial dysfunction through the Ca²⁺/VDAC1/mPTP pathway. Targeting TRPM7-mediated Ca²⁺ signaling may represent a potential therapeutic strategy for preserving glial function in metabolic disease.

PMID:42413641 | DOI:10.1016/j.cellsig.2026.112728