scholarly journals Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

2019 ◽  
Vol 27 (5) ◽  
pp. 1588-1603 ◽  
Author(s):  
Nicoletta Plotegher ◽  
Dany Perocheau ◽  
Ruggero Ferrazza ◽  
Giulia Massaro ◽  
Gauri Bhosale ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Mitochondrial Membrane ◽  
Lysosomal Storage Disorder ◽  
Calcium Overload ◽  
Lysosomal Storage ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Deregulation ◽  
Calcium Uniporter ◽  
Cellular Bioenergetics ◽  
Radical Generation

Abstract Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson’s disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1−/−) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca2+]c responses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca2+ uptake was reduced in gba1−/− cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1−/− neurons. Behavior of gba1+/− neurons was similar to gba1−/− in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca2+]c dysregulation as mechanisms driving neurodegeneration.

scholarly journals MCUB Regulates the Molecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Stress

Circulation ◽  
2019 ◽  
Vol 140 (21) ◽  
pp. 1720-1733 ◽  
Author(s):  
Jonathan P. Lambert ◽  
Timothy S. Luongo ◽  
Dhanendra Tomar ◽  
Pooja Jadiya ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Calcium Overload ◽  
Molecular Composition ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter

scholarly journals Structure and reconstitution of a MCU-EMRE mitochondrial Ca2+ uniporter complex

2020 ◽  
Author(s):  
Chongyuan Wang ◽  
Rozbeh Baradaran ◽  
Stephen Barstow Long
Keyword(s):  
Mitochondrial Membrane ◽  
Transmembrane Domain ◽  
Functional Unit ◽  
Transmembrane Helix ◽  
Coiled Coil ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
The Matrix ◽  
Ion Pore

AbstractThe proteins MCU and EMRE form the minimal functional unit of the mitochondrial calcium uniporter complex in metazoans, a highly selective and tightly controlled Ca2+ channel of the inner mitochondrial membrane that regulates cellular metabolism. Here we present functional reconstitution of an MCU-EMRE complex from the red flour beetle, Tribolium castaneum, and a cryo-EM structure of the complex at 3.5 Å resolution. Robust Ca2+ uptake is observed into proteoliposomes containing the purified complex and is dependent on EMRE. The structure reveals a tetrameric channel with a single ion pore. EMRE is located at the periphery of the transmembrane domain and associates primarily with the first transmembrane helix of MCU. Coiled coil and juxtamembrane domains within the matrix portion of the complex adopt markedly different conformations than in a structure of a human MCU-EMRE complex, suggesting that the structures represent different conformations of these functionally similar metazoan channels.

scholarly journals Emerging insights into the mechanistic link between α-synuclein and glucocerebrosidase in Parkinson's disease

2013 ◽  
Vol 41 (6) ◽  
pp. 1509-1512 ◽  
Author(s):  
Ryan P. McGlinchey ◽  
Jennifer C. Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Risk Factor ◽  
Present Article ◽  
Clinical Studies ◽  
Genetic Risk ◽  
Lewy Body ◽  
Lysosomal Storage Disorder ◽  
Lysosomal Storage ◽  
Gene Encoding

Mutations in the GBA1 gene, encoding the enzyme glucocerebrosidase, cause the lysosomal storage disorder GD (Gaucher’s disease), and are associated with the development of PD (Parkinson's disease) and other Lewy body disorders. Interestingly, GBA1 variants are the most common genetic risk factor associated with PD. Although clinical studies argue a strong case towards a link between GBA1 mutations and the development of PD, mechanistic insights have been lacking. In the present article, we review recent findings that have provided some biochemical evidence to bridge this relationship, focusing on the molecular link between two proteins, α-synuclein and glucocerebrosidase, involved in PD and GD respectively.

scholarly journals Mitochondrial Calcium Entry Is Essential in Agonist-Induced Procoagulant Platelet Formation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3721-3721
Author(s):  
Andaleb Kholmukhamedov ◽  
Rae Janecke ◽  
Hyojung Choo ◽  
Shawn M Jobe
Keyword(s):  
Mitochondrial Membrane ◽  
Transmembrane Potential ◽  
Calcium Entry ◽  
Mitochondrial Transmembrane Potential ◽  
Mitochondrial Calcium ◽  
Mitochondrial Matrix ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter ◽  
Platelet Formation

Abstract Procoagulant platelets are a subpopulation of activated platelets with high-level phosphatidylserine (PSer) externalization. When initiated by co-stimulation with thrombin (THR) and a GPVI agonist, such as convulxin (CVX) or collagen, both extracellular calcium entry and mitochondrial permeability transition pore (mPTP) formation are required to mediate the transition to the procoagulant platelet phenotype. The intracellular mechanisms coordinating these processes remain unclear. Here we investigated the role of the mitochondrial calcium uniporter in the regulation of procoagulant platelet formation. The flux of calcium from the cytosol to the mitochondrial matrix is limited by the ion-impermeable inner mitochondrial membrane. Initially, a pharmacologic approach was utilized to investigate the importance of mitochondrial calcium entry and elevation. Washed human or murine platelets were stimulated with THR and/or CVX in physiologic buffer with 2 mM CaCl2. Mitochondrial transmembrane potential was evaluated using 0.5 μM tetramethylrhodamine methylester (TMRM). Limitation of mitochondrial calcium entry either through alteration of pre-stimulatory mitochondrial membrane potential (i.e. inhibition of F0F1 ATP-ase, mitochondrial uncoupling etc.) or using the ruthenium red analog (Ru360) abrogated both mPTP and procoagulant platelet formation consistent with the hypothesis that elevated calcium levels within the mitochondrial matrix drives these processes. The molecular pathway mediating this rapid mechanism of calcium entry was investigated using mitochondrial calcium uniporter (MCU) null platelets. MCU is a transmembrane ion channel that allows the passage of Ca2+ from the cytosol into the mitochondrial matrix. Neither platelet aggregatory ability nor granule release was altered in response to single or dual-agonist stimulation. In contrast, procoagulant platelet formation in MCU null platelets was significantly decreased coincident with decreased mPTP formation as measured by loss of mitochondrial transmembrane potential. Whereas the number of annexin V positive platelets decreased from 60% in WT to 32% in MCU null (p<0.05, n=4). Thus, these results identify a key role of mitochondrial calcium uptake channel in the regulation of strong agonist-initiated procoagulant platelet formation and suggest a novel pharmacologic target that could be used the treatment of procoagulant-platelet related pathologies. Disclosures No relevant conflicts of interest to declare.

scholarly journals The mechanism of MICU-dependent gating of the mitochondrial Ca2+uniporter

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Vivek Garg ◽  
Junji Suzuki ◽  
Ishan Paranjpe ◽  
Tiffany Unsulangi ◽  
Liron Boyman ◽  
...  
Keyword(s):  
Mitochondrial Membrane ◽  
Comprehensive Analysis ◽  
Intermembrane Space ◽  
Inner Mitochondrial Membrane ◽  
Rigorous Analysis ◽  
Regulatory Subunits ◽  
Mitochondrial Calcium Uniporter ◽  
Isolated Mitochondria ◽  
Calcium Uniporter ◽  
Selective Channel

Ca2+ entry into mitochondria is through the mitochondrial calcium uniporter complex (MCUcx), a Ca2+-selective channel composed of five subunit types. Two MCUcx subunits (MCU and EMRE) span the inner mitochondrial membrane, while three Ca2+-regulatory subunits (MICU1, MICU2, and MICU3) reside in the intermembrane space. Here, we provide rigorous analysis of Ca2+ and Na+ fluxes via MCUcx in intact isolated mitochondria to understand the function of MICU subunits. We also perform direct patch clamp recordings of macroscopic and single MCUcx currents to gain further mechanistic insights. This comprehensive analysis shows that the MCUcx pore, composed of the EMRE and MCU subunits, is not occluded nor plugged by MICUs during the absence or presence of extramitochondrial Ca2+ as has been widely reported. Instead, MICUs potentiate activity of MCUcx as extramitochondrial Ca2+ is elevated. MICUs achieve this by modifying the gating properties of MCUcx allowing it to spend more time in the open state.

288-LB: Effects of the Hepatic Mitochondrial Calcium Uniporter on Hepatic Gluconeogenesis and Mitochondrial Metabolism in Awake Mice

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 288-LB
Author(s):  
JI EUN LEE ◽  
LEIGH GOEDEKE ◽  
YE ZHANG ◽  
RACHEL J. PERRY ◽  
RUSSELL GOODMAN ◽  
...  
Keyword(s):  
Mitochondrial Metabolism ◽  
Mitochondrial Calcium ◽  
Hepatic Gluconeogenesis ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter
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