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A connection in life and death: The BCL-2 family coordinates mitochondrial network dynamics and stem cell fate.
Rasmussen ML, Gama V
(2020) Int Rev Cell Mol Biol 353: 255-284
MeSH Terms: Animals, Cell Death, Cell Differentiation, Humans, Mitochondria, Mitochondrial Dynamics, Proto-Oncogene Proteins c-bcl-2, Stem Cells
Show Abstract · Added August 24, 2020
The B cell CLL/lymphoma-2 (BCL-2) family of proteins control the mitochondrial pathway of apoptosis, also known as intrinsic apoptosis. Direct binding between members of the BCL-2 family regulates mitochondrial outer membrane permeabilization (MOMP) after an apoptotic insult. The ability of the cell to sense stress and translate it into a death signal has been a major theme of research for nearly three decades; however, other mechanisms by which the BCL-2 family coordinates cellular homeostasis beyond its role in initiating apoptosis are emerging. One developing area of research is understanding how the BCL-2 family of proteins regulate development using pluripotent stem cells as a model system. Understanding BCL-2 family-mediated regulation of mitochondrial homeostasis in cell death and beyond would uncover new facets of stem cell maintenance and differentiation potential.
© 2020 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
8 MeSH Terms
A Non-apoptotic Function of MCL-1 in Promoting Pluripotency and Modulating Mitochondrial Dynamics in Stem Cells.
Rasmussen ML, Kline LA, Park KP, Ortolano NA, Romero-Morales AI, Anthony CC, Beckermann KE, Gama V
(2018) Stem Cell Reports 10: 684-692
MeSH Terms: Apoptosis, Cell Differentiation, Cell Line, Cellular Reprogramming, Humans, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membranes, Myeloid Cell Leukemia Sequence 1 Protein, Pluripotent Stem Cells, Proto-Oncogene Proteins c-bcl-2
Show Abstract · Added March 14, 2018
Human pluripotent stem cells (hPSCs) maintain a highly fragmented mitochondrial network, but the mechanisms regulating this phenotype remain unknown. Here, we describe a non-cell death function of the anti-apoptotic protein, MCL-1, in regulating mitochondrial dynamics and promoting pluripotency of stem cells. MCL-1 is induced upon reprogramming, and its inhibition or knockdown induces dramatic changes to the mitochondrial network as well as loss of the key pluripotency transcription factors, NANOG and OCT4. Aside from localizing at the outer mitochondrial membrane like other BCL-2 family members, MCL-1 is unique in that it also resides at the mitochondrial matrix in pluripotent stem cells. Mechanistically, we find MCL-1 to interact with DRP-1 and OPA1, two GTPases responsible for remodeling the mitochondrial network. Depletion of MCL-1 compromised the levels and activity of these key regulators of mitochondrial dynamics. Our findings uncover an unexpected, non-apoptotic function for MCL-1 in the maintenance of mitochondrial structure and stemness.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Homeostatic Responses Regulate Selfish Mitochondrial Genome Dynamics in C. elegans.
Gitschlag BL, Kirby CS, Samuels DC, Gangula RD, Mallal SA, Patel MR
(2016) Cell Metab 24: 91-103
MeSH Terms: Animals, Caenorhabditis elegans, DNA, Mitochondrial, Gene Deletion, Gene Dosage, Genome, Mitochondrial, Homeostasis, Mitochondrial Dynamics, Mutation, RNA Interference, Transcription, Genetic, Unfolded Protein Response
Show Abstract · Added March 21, 2018
Mutant mitochondrial genomes (mtDNA) can be viewed as selfish genetic elements that persist in a state of heteroplasmy despite having potentially deleterious metabolic consequences. We sought to study regulation of selfish mtDNA dynamics. We establish that the large 3.1-kb deletion-bearing mtDNA variant uaDf5 is a selfish genome in Caenorhabditis elegans. Next, we show that uaDf5 mutant mtDNA replicates in addition to, not at the expense of, wild-type mtDNA. These data suggest the existence of a homeostatic copy-number control that is exploited by uaDf5 to "hitchhike" to high frequency. We also observe activation of the mitochondrial unfolded protein response (UPR(mt)) in uaDf5 animals. Loss of UPR(mt) causes a decrease in uaDf5 frequency, whereas its constitutive activation increases uaDf5 levels. UPR(mt) activation protects uaDf5 from mitophagy. Taken together, we propose that mtDNA copy-number control and UPR(mt) represent two homeostatic response mechanisms that play important roles in regulating selfish mitochondrial genome dynamics.
Copyright © 2016 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
12 MeSH Terms
CHIP Is an Essential Determinant of Neuronal Mitochondrial Stress Signaling.
Palubinsky AM, Stankowski JN, Kale AC, Codreanu SG, Singer RJ, Liebler DC, Stanwood GD, McLaughlin B
(2015) Antioxid Redox Signal 23: 535-49
MeSH Terms: Animals, Autophagy, Cell Hypoxia, Cells, Cultured, Glucose, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Dynamics, Neurons, Oxidation-Reduction, Protein Biosynthesis, Rats, Sprague-Dawley, Signal Transduction, Stress, Physiological, Ubiquitin-Protein Ligases
Show Abstract · Added January 26, 2015
AIMS - Determine the mechanism by which C-terminus of HSC70-interacting protein (CHIP) induction alters neuronal survival under conditions of mitochondrial stress induced by oxygen glucose deprivation.
RESULTS - We report that animals deficient in the E3 ubiquitin ligase, CHIP, have high baseline levels of central nervous system protein oxidation and lipid peroxidation, reduced antioxidant defenses, and decreased energetic status. Stress-associated molecules typically linked to Parkinson's disease such as the mitochondrial kinase, PTEN-inducible putative kinase 1 (PINK1), and another E3 ligase, Parkin, are upregulated in brains from CHIP knockout (KO) animals. Utilizing a novel biotin-avidin capture technique, we found that the oxidation status of Parkin and the mitochondrial fission protein, dynamin-related protein 1 (Drp1), are altered in a CHIP-dependent manner. We also found that following oxygen-glucose deprivation (OGD), the expression of CHIP, PINK1, and the autophagic marker, LC3, increase and there is activation of the redox-sensitive kinase p66(shc). Under conditions of OGD, CHIP relocalizes from the cytosol to mitochondria. Mitochondria from CHIP KO mice have profound impairments in stress response induced by calcium overload, resulting in accelerated permeability transition activity. While CHIP-deficient neurons are morphologically intact, they are more susceptible to OGD consistent with a previously unknown neuroprotective role for CHIP in maintaining mitochondrial homeostasis.
INNOVATION - CHIP relocalization to the mitochondria is essential for the regulation of mitochondrial integrity and neuronal survival following OGD.
CONCLUSIONS - CHIP is an essential regulator of neuronal bioenergetics and redox tone. Altering the expression of this protein has profound effects on neuronal survival when cells are exposed to OGD.
1 Communities
3 Members
0 Resources
17 MeSH Terms
Mitochondrial dynamics: regulatory mechanisms and emerging role in renal pathophysiology.
Zhan M, Brooks C, Liu F, Sun L, Dong Z
(2013) Kidney Int 83: 568-81
MeSH Terms: Animals, Apoptosis, Humans, Kidney, Kidney Diseases, Mitochondria, Mitochondrial Dynamics, Mitophagy, Signal Transduction
Show Abstract · Added September 12, 2016
Mitochondria are a class of dynamic organelles that constantly undergo fission and fusion. Mitochondrial dynamics is governed by a complex molecular machinery and finely tuned by regulatory proteins. During cell injury or stress, the dynamics is shifted to fission, resulting in mitochondrial fragmentation, which contributes to mitochondrial damage and consequent cell injury and death. Emerging evidence has suggested a role of mitochondrial fragmentation in the pathogenesis of renal diseases including acute kidney injury and diabetic nephropathy. A better understanding of the regulation of mitochondrial dynamics and its pathogenic changes may unveil novel therapeutic strategies.
1 Communities
1 Members
0 Resources
9 MeSH Terms