Calcium transport by rat brain mitochondria and oxidation of 2-oxoglutarate

Bernard, Phyllis A.; Cockrell, Ronald S.

doi:10.1016/0005-2728(84)90113-0

Cited by 9 publications

(5 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is supported by data that show complex I activity is reduced after reperfusion injury [22]. Others have reported that calcium overload inhibits the matrix dehydrogenase complexes pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase [23–25]. In addition to these reports, others have claimed calcium overload directly inhibits the adenine nucleotide translocase [26], reduces the availability of free and/or Mg-bound ADP for oxidative phosphorylation and transport caused by calcium chelation [27, 28], causes net loss of matrix purine nucleotides [29], or lowers the membrane potential for ATP production [30].…”

Section: Introductionmentioning

confidence: 70%

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

et al. 2019

View full text Add to dashboard Cite

Early studies have shown that moderate levels of calcium overload can cause lower oxidative phosphorylation rates. However, the mechanistic interpretations of these findings were inadequate. And while the effect of excessive calcium overload on mitochondrial function is well appreciated, there has been little to no reports on the consequences of low to moderate calcium overload. To resolve this inadequacy, mitochondrial function from guinea pig hearts was quantified using several well-established methods including high-resolution respirometry and spectrofluorimetry and analyzed using mathematical modeling. We measured key mitochondrial variables such as respiration, mitochondrial membrane potential, buffer calcium, and substrate effects for a range of mitochondrial calcium loads from near zero to levels approaching mitochondrial permeability transition. In addition, we developed a computer model closely mimicking the experimental conditions and used this model to design experiments capable of eliminating many hypotheses generated from the data analysis. We subsequently performed those experiments and determined why mitochondrial ADP-stimulated respiration is significantly lowered during calcium overload. We found that when calcium phosphate levels, not matrix free calcium, reached sufficient levels, complex I activity is inhibited, and the rate of ATP synthesis is reduced. Our findings suggest that calcium phosphate granules form physical barriers that isolate complex I from NADH, disrupt complex I activity, or destabilize cristae and inhibit NADH-dependent respiration.

show abstract

Section: Introductionmentioning

confidence: 70%

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Further, mitochondrial calcium levels can directly influence OXPHOS activity as calcium is a cofactor for multiple metabolic enzymes [20, 21]. Calcium overload in the mitochondrial matrix has been shown to suppress OXPHOS activity by inhibiting the activity of key metabolic enzymes and electron transport chain activity [22–30]. Similarly, insufficient calcium can also reduce OXPHOS activity [31, 32].…”

Section: Introductionmentioning

confidence: 99%

“…Calcium overload in the mitochondrial matrix has been shown to suppress OXPHOS activity by inhibiting the activity of key metabolic enzymes and electron transport chain activity [22][23][24][25][26][27][28][29][30].…”

Section: Introductionmentioning

confidence: 99%

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

Sheth,

Engel,

Tolison

et al. 2023

Preprint

View full text Add to dashboard Cite

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance.SignificanceWe identify increased utilization of mitochondrial calcium as distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.

show abstract

“…The normal concentration of calcium in the cytoplasm of brain parenchymal cells (pyramidal cells, astrocytes, glia, etc.) is in the range of 100 nM, while the concentration of calcium in the mitochondria is greater (2). Brain ischemia can produce an extra load of calcium ions that need to be pumped out of the ischemic cells, which alters the delicate energy balance.…”

Section: Introductionmentioning

confidence: 99%

“…Brain ischemia can produce an extra load of calcium ions that need to be pumped out of the ischemic cells, which alters the delicate energy balance. Furthermore, the elevated concentration of calcium in the mitochondria has an inhibitory effect on respiration (2). As the speed of oxidative phosphorylation decreases, the role of glycolytic ATP production increases, causing a massive intracellular lactic acidosis-thus creating another viscious cycle, i.e., promotion of the continuous formation of lactic acid.…”

Section: Introductionmentioning

confidence: 99%

³¹P and ¹H NMR spectroscopy to study the effects of Gallopamil on brain ischemia

Ligeti

Osbakken

Subramanian

et al. 1987

Magnetic Resonance in Med

View full text Add to dashboard Cite

Studies were performed on 16 cats to evaluate the potential protective effects of Gallopamil on brain ischemia. Brain energy state was determined by 31P NMR and lactate concentration was determined by 1H NMR. Double-tuned surface coils (tuned to 35.8 and 88.4, respectively) were placed on the head after skin and muscle were removed from the calvarium. A 2.1-T, 25-cm-bore Oxford magnet interfaced to a Phosphoenergetics 250-80 spectrometer was used. The cats were bled to 50 mm Hg for 10 min with subsequent application of bilateral carotid occlusion for 10 min to produce ischemia. In all animals, brain energy state as measured by Pi/PCr and lactate concentrations were determined over 5-min intervals (before, during, and after the onset of ischemia). While Gallopamil did not prevent decreases in brain energy state or attenuate the rise in lactate concentration seen during ischemia, brain from animals treated with Gallopamil had a more rapid return of pHi to baseline during the recovery period. In Gallopamil-treated cats, higher levels of lactate were necessary to cause a similar decrease in pHi when compared to controls. The rate of lactate recovery to baseline levels was similar in both groups (control = -0.38 +/- 0.14 mM/min; Gallopamil = -0.44 +/- 0.32 mM/min). In conclusion, Gallopamil appears to lessen the acidosis caused by cerebral ischemia. In addition, we have demonstrated that multinuclear NMR spectroscopy is a powerful tool to study the effects of drugs on cerebral metabolism.

show abstract

Calcium transport by rat brain mitochondria and oxidation of 2-oxoglutarate

Cited by 9 publications

References 23 publications

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

³¹P and ¹H NMR spectroscopy to study the effects of Gallopamil on brain ischemia

Contact Info

Product

Resources

About

Calcium transport by rat brain mitochondria and oxidation of 2-oxoglutarate

Cited by 9 publications

References 23 publications

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

Calcium phosphate precipitation inhibits mitochondrial energy metabolism

Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

31P and 1H NMR spectroscopy to study the effects of Gallopamil on brain ischemia

Contact Info

Product

Resources

About

³¹P and ¹H NMR spectroscopy to study the effects of Gallopamil on brain ischemia