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Biological regulatory network analysis for targeting the mitochondrial calcium uniporter (MCU) mediated calcium (Ca 2+ ) transport in neurodegenerative disorders.

Umar AmjidUbair AzizUzma HabibIshrat Jabeen
Published in: Cell biochemistry and function (2024)
Calcium (Ca 2+ ) has been observed as the most important ion involved in a series of cellular processes and its homeostasis is critical for normal cellular functions. Mitochondrial calcium uniporter (MCU) complex has been recognized as the most important calcium-specific channel located in the inner mitochondrial membrane and is one of the major players in maintaining the Ca 2+ homeostasis by transporting Ca 2+ across the mitochondrial membrane. Furthermore, dysregulation of the mitochondrial Ca 2+ homeostasis has been orchestrated to neurodegenerative response. This necessitates quantitative evaluation of the MCU-dependent mROS production and subsequent cellular responses for more specific therapeutic interventions against neurodegenerative disorders. Towards this goal, here we present a biological regulatory network of MCU to dynamically simulate the MCU-mediated ROS production and its response in neurodegeneration. Previously, ruthenium complex RuRed and its derivatives have been reported to show low nM to high µM potency against MCU to maintain cytosolic Ca 2+ (cCa 2+ ) homeostasis by modulating mitochondrial Ca 2+ (mCa 2+ ) uptake. Therefore, structural modeling and dynamic simulation of MCU pore-forming subunit is performed to probe the interaction profiling of previously reported Ru265 and its derivatives compounds with MCU. The current study highlighted MCU as a potential drug target in neurodegenerative disorders. Furthermore, ASP261 and GLU264 amino acid residues in DIME motif of MCU pore-forming subunits are identified as crucial for modulating the activity of MCU in neurodegenerative disorders.
Keyphrases
  • oxidative stress
  • protein kinase
  • network analysis
  • transcription factor
  • emergency department
  • dna damage
  • cell death
  • single cell
  • drug delivery
  • single molecule
  • climate change
  • living cells