The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation

Hom, Jennifer; Quintanilla, Rodrigo A.; Hoffman, Donald L.; Bentley, Karen L. de Mesy; Molkentin, Jeffery D.; Sheu, Shey‐Shing; Porter, George A.

doi:10.1016/j.devcel.2011.10.017

Cited by 36 publications

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“…In fact, embryonic cardiomyocytes present immature mitochondria with a more open mPTP and during their differentiation, mPTP closure drives mitochondrial maturation. 34 In our case, mitochondrial remodeling during P19 differentiation is associated with an apparent increased basal closed state of the pore. The reasons for this apparent discrepancy are not known at the moment, but it may be related with the different origins of cells, as well as with the different degree of transformation.…”

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confidence: 46%

“…This metabolic differentiation into a more efficient energetic infrastructure was also observed during early cardiomyocyte development. 34 Regulators of pluripotency share points of convergence with targets associated with energy metabolism, which may impact the balance between glycolysis and oxidative metabolism. 35 The activation of the mitochondrial machinery seems to be essential for SCs differentiation 10 and in fact, our results revealed a remodeling in some components of the ETC after RA-induced differentiation including a reduced expression of subunits NDUFB8 and UQCRC2.…”

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confidence: 99%

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Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

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The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies. Embryonal carcinoma cells, including the P19 cell line, are pluripotent cancer stem cells (CSCs) derived from pluripotent germ cell tumors called teratocarcinomas. These have been described as the malignant counterparts of embryonic stem cells (ESCs) and are considered a good model to study stem cell (SC) differentiation. The P19 cell line can be maintained as undifferentiated cells (P19SCs) or differentiated (P19dCs) to any cell type of the three germ layers. Similar to ESCs, P19 cells differentiate with retinoic acid (RA) in a dose-dependent manner and depending on growth conditions. 1 Although differentiation generally yields a mixed population of differentiated cells, P19 cells grown in monolayer and treated with 1 mM RA primarily differentiate in endoderm or mesoderm, while retaining their immortality. 2,3Although some therapeutic approaches for regenerative medicine and to targeting CSCs are based on differentiation 4 and mitochondrial-targeted therapies, 5,6 very little is known about the role of mitochondrial metabolism in SC maintenance and differentiation.7 Several mitochondrial characteristics that distinguish transformed cells from healthy cells have been described, 8 including increased mitochondrial transmembrane electric potential (Dcm), which may result from decreased mitochondrial ATP production under normoxia. Similarly, normal SCs primarily rely on glycolysis for energy supply, although the exact mechanism how this occurs in the presence of oxygen and the relationship between SC metabolism and cell fate control is not yet completely understood. 10Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physi...

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Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

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“…To determine whether the c-subunit ring is necessary for such rapid uncoupling in intact cells, we depleted HEK 293T cells of c-subunit proteins by shRNA (Fig. 4A) and then tested cells for IMM permeabilization using calcein/cobalt quenching (7). After the addition of ionomycin to the control cells, a rapid drop in mitochondrial calcein fluorescence was measured, with a time course correlated with changes seen in FlAsh fluorescence (compare Fig.…”

Section: The C-subunit Leak Channel Undergoes Measurable Conformationalmentioning

confidence: 99%

“…Many studies have described the biophysical and pharmacological features of an IMM pore [the mitochondrial permeability transition pore (mPTP)] that is responsible for a rapid IMM uncoupling, causing osmotic shifts within the mitochondrial matrix in the setting of cellular Ca 2+ dysregulation and adenine nucleotide depletion (1)(2)(3)(4). Some studies suggest that such uncoupling also functions during physiological events and that the mPTP may transiently operate as a Ca 2+ -release channel (5)(6)(7). Although models for the molecular identity of the mPTP have been proposed (8), deletions of putative components, such as adenine nucleotide translocase (ANT) and the voltagedependent anion channel (VDAC), have failed to prevent rapid depolarizations (9).…”

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An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore

Alavian

Beutner²,

Lazrove

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

511

538

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Mitochondria maintain tight regulation of inner mitochondrial membrane (IMM) permeability to sustain ATP production. Stressful events cause cellular calcium (Ca 2+ ) dysregulation followed by rapid loss of IMM potential known as permeability transition (PT), which produces osmotic shifts, metabolic dysfunction, and cell death. The molecular identity of the mitochondrial PT pore (mPTP) was previously unknown. We show that the purified reconstituted c-subunit ring of the F O of the F 1 F O ATP synthase forms a voltage-sensitive channel, the persistent opening of which leads to rapid and uncontrolled depolarization of the IMM in cells. Prolonged high matrix Ca 2+ enlarges the c-subunit ring and unhooks it from cyclophilin D/cyclosporine A binding sites in the ATP synthase F 1 , providing a mechanism for mPTP opening. In contrast, recombinant F 1 beta-subunit applied exogenously to the purified c-subunit enhances the probability of pore closure. Depletion of the c-subunit attenuates Ca 2+ -induced IMM depolarization and inhibits Ca 2+ and reactive oxygen species-induced cell death whereas increasing the expression or single-channel conductance of the c-subunit sensitizes to death. We conclude that a highly regulated c-subunit leak channel is a candidate for the mPTP. Beyond cell death, these findings also imply that increasing the probability of c-subunit channel closure in a healthy cell will enhance IMM coupling and increase cellular metabolic efficiency.metabolism | necrosis | apoptosis | ion channel | excitotoxicity M itochondria produce ATP by oxidative phosphorylation (OXPHOS). Leak currents in the inner mitochondrial membrane (IMM) reduce the efficiency of this process by uncoupling the electron transport system from ATP synthase activity. Many studies have described the biophysical and pharmacological features of an IMM pore [the mitochondrial permeability transition pore (mPTP)] that is responsible for a rapid IMM uncoupling, causing osmotic shifts within the mitochondrial matrix in the setting of cellular Ca 2+ dysregulation and adenine nucleotide depletion (1-4). Some studies suggest that such uncoupling also functions during physiological events and that the mPTP may transiently operate as a Ca 2+ -release channel (5-7). Although models for the molecular identity of the mPTP have been proposed (8), deletions of putative components, such as adenine nucleotide translocase (ANT) and the voltagedependent anion channel (VDAC), have failed to prevent rapid depolarizations (9). In the meantime, nonpore forming regulatory components of the mPTP, such as cyclophilin D (CypD), have been extensively investigated (10, 11).We recently reported a leak conductance sensitive to ATP/ ADP and the Bcl-2 family member B-cell lymphoma-extra large (Bcl-x L ) within the membrane of isolated submitochondrial vesicles (SMVs) enriched in ATP synthase (12, 13). We demonstrated binding of Bcl-x L within F 1 to the beta-subunit of the ATP synthase, suggesting that the channel responsible for the leak conductance lies within the memb...

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“…the emergence of embryonic blood stem cells or differentiation of embryonic cardiomyocytes (Harris et al, 2013;Hernández-García et al, 2010;Hom et al, 2011). There is also increasing evidence that ROS are implicated at many distinct levels of biological processes, from gene expression and protein translation to protein-protein interactions, etc.…”

Section: Introductionmentioning

confidence: 99%

Stem cells and the impact of ROS signaling

2014

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An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.

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The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation

Cited by 36 publications

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Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore

Stem cells and the impact of ROS signaling

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The Permeability Transition Pore Controls Cardiac Mitochondrial Maturation and Myocyte Differentiation

Cited by 36 publications

References 0 publications

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

An uncoupling channel within the c-subunit ring of the F 1 F O ATP synthase is the mitochondrial permeability transition pore

Stem cells and the impact of ROS signaling

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An uncoupling channel within the c-subunit ring of the F ₁ F _O ATP synthase is the mitochondrial permeability transition pore