Difference between revisions of "Kushnareva 2013 Cell Death Differ"

Latest revision as of 15:02, 13 November 2017

Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E (2013) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20:353-65.

» PMID:23138851 Open Access

Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E (2013) Cell Death Differ

Abstract: Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca₂₊ retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca₂₊ transients and corresponding reduction of NAD(+) to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca₂₊ and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca₂₊ homeostasis. • Keywords: Calcium, Mitochondria, OPA1

Labels: MiParea: Respiration, Patients

Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell, HeLa Preparation: Intact cells, Permeabilized cells

Regulation: Calcium Coupling state: LEAK, ROUTINE, OXPHOS, ET Pathway: N, S

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 {{Publication
-|title=Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E (2015) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20:353-65.
+|title=Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E (2013) Loss of OPA1 disturbs cellular calcium homeostasis and sensitizes for excitotoxicity. Cell Death Differ 20:353-65.
-|info=[http://www.ncbi.nlm.nih.gov/pubmed/23138851 PMID:23138851]
+|info=[http://www.ncbi.nlm.nih.gov/pubmed/23138851 PMID:23138851 Open Access]
 |authors=Kushnareva YE, Gerencser AA, Bossy B, Ju WK, White AD, Waggoner J, Ellisman MH, Perkins G, Bossy-Wetzel E
-|year=2015
+|year=2013
 |journal=Cell Death Differ
-|abstract=Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve
+|abstract=Optic atrophy 1 ''(OPA1)'' mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca<sub>2+</sub> retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca<sub>2+</sub> transients and corresponding reduction of NAD(+) to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca<sub>2+</sub> and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca<sub>2+</sub> homeostasis.
-degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we
+|keywords=Calcium, Mitochondria, OPA1
-reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation,
-deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca2þ retention capacity, reduced
-mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista
-junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells
-exhibit decreased agonist-evoked mitochondrial Ca2þ transients and corresponding reduction of NADþ to NADH, but the
-impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in
-RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca2þ and sensitizes RGCs to
-excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating
-partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that
-whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of
-OPA1 also results in defective Ca2þ homeostasis.
-|keywords=Calcium, Mitochondria, OPA
 }}
 {{Labeling
 |area=Respiration, Patients
 |organism=Human
-|tissues=Endothelial;epithelial;mesothelial cell
+|tissues=Endothelial;epithelial;mesothelial cell, HeLa
-|model cell lines=HeLa
 |preparations=Intact cells, Permeabilized cells
-|couplingstates=LEAK, ROUTINE, OXPHOS, ETS
+|topics=Calcium
-|substratestates=CI, CII
+|couplingstates=LEAK, ROUTINE, OXPHOS, ET
+|pathways=N, S
 }}