regulation of calcium import into the mitochondrion
Definition
Target type: biologicalprocess
Any process that modulates the frequency, rate or extent of calcium import into the mitochondrion. [GOC:sl, PMID:24085037]
Calcium import into mitochondria is a tightly regulated process crucial for maintaining cellular homeostasis and signaling. The primary route for calcium entry into the mitochondrial matrix is through the mitochondrial calcium uniporter (MCU), a highly selective ion channel located in the inner mitochondrial membrane.
The MCU is a multi-protein complex, with MCU being the pore-forming subunit. It is regulated by several factors, including:
* **Electrochemical gradient:** The high negative potential across the inner mitochondrial membrane drives calcium influx.
* **Microenvironment:** Local calcium concentration gradients near the MCU play a significant role. The presence of other proteins, such as MICU1 and MICU2, can modulate calcium sensitivity and selectivity of the MCU.
* **Post-translational modifications:** Phosphorylation of MCU by kinases like CaMKII can enhance its activity.
* **Mitochondrial membrane potential:** A high membrane potential is required for optimal calcium uptake.
* **Other regulatory proteins:** Several other proteins, including MCUR1, EMRE, and SLC25A24, interact with MCU and influence its activity.
The influx of calcium into the mitochondrial matrix triggers a series of events, including:
* **Activation of mitochondrial enzymes:** Calcium is a critical cofactor for several key enzymes in the citric acid cycle, such as pyruvate dehydrogenase and isocitrate dehydrogenase, promoting ATP production.
* **Regulation of mitochondrial respiration:** Calcium influx can stimulate mitochondrial respiration by enhancing electron transport chain activity.
* **Induction of apoptosis:** High levels of calcium in the mitochondrial matrix can trigger the release of cytochrome c, leading to apoptosis.
In addition to the MCU, other pathways for calcium entry into mitochondria exist, including:
* **Sodium-calcium exchange (NCX):** This transporter utilizes the sodium gradient to bring calcium into the mitochondria.
* **Calcium-dependent anion channels (VDACs):** These channels can allow calcium influx in response to specific stimuli.
The regulation of calcium import into mitochondria is a complex and multifaceted process involving multiple proteins and signaling pathways. It plays a critical role in maintaining cellular function and responding to stress conditions.'
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Proteins (1)
| Protein | Definition | Taxonomy |
|---|---|---|
| Presenilin-2 | A presenilin-2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P49810] | Homo sapiens (human) |
Compounds (21)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| 7-amino-4-chloro-3-methoxy-2-benzopyran-1-one | isocoumarins | ||
| tarenflurbil | tarenflurbil: R-enantiomer of flurbiprofen but not a COX inhibitor; modulates NF-kB, gamma-secretase, amyloid beta-protein; | flurbiprofen | |
| cholanic acid | 5beta-cholanic acids; cholanic acid | ||
| t0901317 | T0901317: an LXRalpha and LXRbeta agonist | ||
| n-(n-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester | DAPT : A dipeptide consisting of alanylphenylglycine derivatised as a 3,5-difluorophenylacetamide at the amino terminal and a tert-butyl ester at the carboxy terminal. A gamma-secretase inhibitor. | carboxylic ester; difluorobenzene; dipeptide; tert-butyl ester | EC 3.4.23.46 (memapsin 2) inhibitor |
| sulindac sulfide | sulindac sulfide : An aryl sulfide that is a metabolite of sulindac. A non-steroidal anti-inflammatory drug, which also has anticancer activity. sulindac sulfide: sulfated analog of indomethacin & inhibitor of prostaglandin synthesis in vitro; RN given refers to cpd without isomeric designation; structure given in first source | aryl sulfide; monocarboxylic acid; organofluorine compound | antineoplastic agent; apoptosis inducer; non-steroidal anti-inflammatory drug |
| l 685458 | L 685458: a gamma-secretase inhibitor; structure in first source L-685,458 : A peptide and carboxamide that is L-leucyl-L-phenylalaninamide, L-Leu-L-Phe-NH2, which has been acylated on the N-terminus by a Phe-Phe hydroxyethylene dipeptide isotere, 2R-benzyl-5S-tert-butoxycarbonylamino-4R-hydroxy-6-phenylhexanoic acid. Compounds based on the structure of L-685,458 are potent inhibitors of gamma-secretase, which mediates the final catalytic step that generates the amyloid beta-peptide (Abeta), which assembles into the neurotoxic aggregates in the brains of sufferers of Alzheimer's disease. | carbamate ester; monocarboxylic acid amide; peptide; secondary alcohol | EC 3.4.23.46 (memapsin 2) inhibitor; peptidomimetic |
| mk 0752 | |||
| ly 450139 | peptide | ||
| chf 5074 | 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid: a beta-amyloid(1-42) lowering agent; structure in first source | ||
| ly 411575 | dibenzoazepine; difluorobenzene; lactam; secondary alcohol | EC 3.4.23.46 (memapsin 2) inhibitor | |
| 4-(2-((1r)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid | sulfonamide | ||
| begacestat | |||
| e 2012 | |||
| mrk 560 | MRK 560: a gamma-secretase inhibitor; MRK-560 is the (cis)-isomer; structure in first source | ||
| 1, 3-di-(n-carboxybenzoyl-leucyl-leucyl)amino acetone | 1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone: structure in first source | ||
| pf 3084014 | nirogacestat : A member of the class of imidazoles that is 1H-imidazole substituted by a 1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl group at position 1 and a {N-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-L-norvalyl}amino group at position 4. It is a gamma-secretase inhibitor whose hydrobromide salt is indicated for adult patients with progressing desmoid tumours who require systemic treatment. nirogacestat: an antineoplastic agent | ||
| bms 708163 | BMS 708163: structure in first source | oxadiazole; ring assembly | |
| ro 4929097 | dibenzoazepine; dicarboxylic acid diamide; lactam; organofluorine compound | EC 3.4.23.46 (memapsin 2) inhibitor | |
| jnj 40418677 | |||
| (r)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1h-pyrazolo(4,3-c)quinoline | (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline: gamma secretase inhibitor; structure in first source |