scholarly journals MCL-1 inhibition by selective BH3 mimetics disrupts mitochondrial dynamics in iPSC-derived cardiomyocytes

2019 ◽  
Author(s):  
Megan L. Rasmussen ◽  
Nilay Taneja ◽  
Abigail C. Neininger ◽  
Lili Wang ◽  
Linzheng Shi ◽  
...  
Keyword(s):  
Pluripotent Stem Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Outer Mitochondrial Membrane ◽  
Canonical Function ◽  
Bh3 Mimetics ◽  
Caspase Inhibition ◽  
Dynamics And Function ◽  
Apoptotic Activity ◽  
And Function

SummaryMCL-1 is a well characterized inhibitor of cell death that has also been shown to be a regulator of mitochondrial dynamics in human pluripotent stem cells (hPSCs). We used cardiomyocytes derived from hPSCs (hPSC-CMs) to uncover whether MCL-1 is crucial for cardiac function and survival. Inhibition of MCL-1 by BH3 mimetics, resulted in the disruption of mitochondrial morphology and dynamics as well as disorganization of the actin cytoskeleton. Interfering with MCL-1 function affects the homeostatic proximity of DRP-1 and MCL-1 at the outer mitochondrial membrane, resulting in decreased functionality of hPSC-CMs. BH3 mimetics targeting MCL-1 are promising anti-tumor therapeutics. Cardiomyocytes display abnormal functional cardiac performance even after caspase inhibition, supporting a non-apoptotic activity of MCL-1 in hPSC-CMs. Progression towards using BCL-2 family inhibitors, especially targeting MCL-1, depends on understanding not only its canonical function in preventing apoptosis, but also in the maintenance of mitochondrial dynamics and function.

scholarly journals Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jessica C. Garbern ◽  
Richard T. Lee
Keyword(s):  
Pluripotent Stem Cells ◽  
Fetal Development ◽  
Contractile Function ◽  
Mitochondrial Dynamics ◽  
Nutrient Sensing ◽  
Metabolic Changes ◽  
Complete Development ◽  
Embryonic And Fetal Development ◽  
Dynamics And Function ◽  
And Function

AbstractCurrent methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

scholarly journals FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

2016 ◽  
Vol 311 (6) ◽  
pp. H1540-H1559 ◽  
Author(s):  
Antoine H. Chaanine ◽  
Erik Kohlbrenner ◽  
Scott I. Gamb ◽  
Adam J. Guenzel ◽  
Katherine Klaus ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mitochondrial Dynamics ◽  
Left Ventricular ◽  
Attractive Potential ◽  
Mitochondrial Morphology ◽  
Cardiac Stress ◽  
Virus Serotype ◽  
Dynamics And Function ◽  
And Function

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/ .

scholarly journals Critical requirement of SOS1 RAS-GEF function for mitochondrial dynamics, metabolism, and redox homeostasis

Oncogene ◽  
2021 ◽  
Author(s):  
Rósula García-Navas ◽  
Pilar Liceras-Boillos ◽  
Carmela Gómez ◽  
Fernando C. Baltanás ◽  
Nuria Calzada ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Redox Homeostasis ◽  
Atp Production ◽  
Oxidative Energy Metabolism ◽  
Ras Activation ◽  
Mitochondrial Defects ◽  
Critical Requirement ◽  
Dynamics And Function ◽  
And Function ◽  
And Control

AbstractSOS1 ablation causes specific defective phenotypes in MEFs including increased levels of intracellular ROS. We showed that the mitochondria-targeted antioxidant MitoTEMPO restores normal endogenous ROS levels, suggesting predominant involvement of mitochondria in generation of this defective SOS1-dependent phenotype. The absence of SOS1 caused specific alterations of mitochondrial shape, mass, and dynamics accompanied by higher percentage of dysfunctional mitochondria and lower rates of electron transport in comparison to WT or SOS2-KO counterparts. SOS1-deficient MEFs also exhibited specific alterations of respiratory complexes and their assembly into mitochondrial supercomplexes and consistently reduced rates of respiration, glycolysis, and ATP production, together with distinctive patterns of substrate preference for oxidative energy metabolism and dependence on glucose for survival. RASless cells showed defective respiratory/metabolic phenotypes reminiscent of those of SOS1-deficient MEFs, suggesting that the mitochondrial defects of these cells are mechanistically linked to the absence of SOS1-GEF activity on cellular RAS targets. Our observations provide a direct mechanistic link between SOS1 and control of cellular oxidative stress and suggest that SOS1-mediated RAS activation is required for correct mitochondrial dynamics and function.

Does metformin modulate mitochondrial dynamics and function in type 2 diabetic patients?

2021 ◽  
Author(s):  
Aranzazu Martinez de Marañón ◽  
Francisco Gerardo Canet ◽  
Zaida Abad-Jimenez ◽  
Ana Jover ◽  
Carlos Morillas ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Dynamics And Function ◽  
And Function ◽  
Type 2 Diabetic

scholarly journals A comprehensive approach for artifact-free sample preparation and assessment of mitochondrial morphology in tissue and cultured cells

2021 ◽  
Author(s):  
Antentor Hinton ◽  
Prasanna Katti ◽  
Trace A. Christensen ◽  
Margaret Mungai ◽  
Jianqiang Shao ◽  
...  
Keyword(s):  
Structural Changes ◽  
Cultured Cells ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Specimen Preparation ◽  
Preparation Methods ◽  
Cellular Environment ◽  
Stress Changes ◽  
Precise Relationship ◽  
And Function

Mitochondrial dynamics and morphology (fission, fusion, and the formation of nanotunnels) are very sensitive to the cellular environment and may be adversely affected by oxidative stress, changes in calcium levels, and hypoxia. Investigating the precise relationship between the organelle structure and function requires methods that can adequately preserve the structure while providing accurate, quantitative measurements of mitochondrial morphological attributes. Here, we demonstrate a practical approach for preserving and measuring fine structural changes in two-dimensional electron micrographs, obtained using transmission electron microscopy, highlighting the specific advantages of this technique. Additionally, this study defines a set of quantifiable metrics that can be applied to measure mitochondrial architecture and other organellar structures. Finally, we validated specimen preparation methods that avoid the introduction of morphological artifacts in mitochondrial appearance that do not require whole-animal perfusion.

scholarly journals A role for keratins in supporting mitochondrial organization and function in skin keratinocytes

2019 ◽  
Author(s):  
Kaylee Steen ◽  
Desu Chen ◽  
Fengrong Wang ◽  
Song Chen ◽  
Surinder Kumar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Metabolic Regulation ◽  
Mouse Skin ◽  
Mitochondrial Morphology ◽  
Null Mouse ◽  
Embryonic Mouse ◽  
Atp Production ◽  
Skin Keratinocytes ◽  
Dynamics And Function ◽  
And Function

AbstractMitochondria fulfill essential roles in ATP production, metabolic regulation, calcium signaling, generation of reactive oxygen species (ROS) and additional determinants of cellular health. Recent studies have highlighted a role for mitochondria during cell differentiation, including in skin epidermis. The observation of oxidative stress in keratinocytes from Krt16 null mouse skin, a model for pachyonychia congenita (PC)-associated palmoplantar keratoderma, prompted us to examine the role of Keratin (K) 16 protein and its partner K6 in regulating the structure and function of mitochondria. Electron microscopy revealed major anomalies in mitochondrial ultrastructure in late stage, E18.5, Krt6a/Krt6b null embryonic mouse skin. Follow-up studies utilizing biochemical, metabolic, and live imaging readouts showed that, relative to controls, skin keratinocytes null for Krt6a/Krt6b or Krt16 exhibit elevated ROS, reduced mitochondrial respiration, intracellular distribution differences and altered movement of mitochondria within the cell. These findings highlight a novel role for K6 and K16 in regulating mitochondrial morphology, dynamics and function and shed new light on the causes of oxidative stress observed in PC and related keratin-based skin disorders.

scholarly journals Mitochondrial Fusion by M1 Promotes Embryoid Body Cardiac Differentiation of Human Pluripotent Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Jarmon G. Lees ◽  
Anne M. Kong ◽  
Yi C. Chen ◽  
Priyadharshini Sivakumaran ◽  
Damián Hernández ◽  
...  
Keyword(s):  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Embryoid Body ◽  
Mitochondrial Dynamics ◽  
Embryoid Bodies ◽  
Mitochondrial Fusion ◽  
Cardiac Differentiation ◽  
Patient Specific ◽  
Mitochondrial Morphology ◽  
Human Ipscs

Human induced pluripotent stem cells (iPSCs) can be differentiated in vitro into bona fide cardiomyocytes for disease modelling and personalized medicine. Mitochondrial morphology and metabolism change dramatically as iPSCs differentiate into mesodermal cardiac lineages. Inhibiting mitochondrial fission has been shown to promote cardiac differentiation of iPSCs. However, the effect of hydrazone M1, a small molecule that promotes mitochondrial fusion, on cardiac mesodermal commitment of human iPSCs is unknown. Here, we demonstrate that treatment with M1 promoted mitochondrial fusion in human iPSCs. Treatment of iPSCs with M1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. The pro-fusion and pro-cardiogenic effects of M1 were not associated with changes in expression of the α and β subunits of adenosine triphosphate (ATP) synthase. Our findings demonstrate for the first time that hydrazone M1 is capable of promoting cardiac differentiation of human iPSCs, highlighting the important role of mitochondrial dynamics in cardiac mesoderm lineage specification and cardiac development. M1 and other mitochondrial fusion promoters emerge as promising molecular targets to generate lineages of the heart from human iPSCs for patient-specific regenerative medicine.

scholarly journals Neuron-based high-content assay and screen for CNS active mitotherapeutics

2020 ◽  
Vol 6 (2) ◽  
pp. eaaw8702 ◽  
Author(s):  
Boglarka H. Varkuti ◽  
Miklos Kepiro ◽  
Ze Liu ◽  
Kyle Vick ◽  
Yosef Avchalumov ◽  
...  
Keyword(s):  
Small Molecule ◽  
Hippocampal Neurons ◽  
Mitochondrial Dynamics ◽  
Synaptic Activity ◽  
Glutamate Toxicity ◽  
Primary Neurons ◽  
Screening Assay ◽  
Dynamics And Function ◽  
Small Molecule Modulators ◽  
And Function

Impaired mitochondrial dynamics and function are hallmarks of many neurological and psychiatric disorders, but direct screens for mitotherapeutics using neurons have not been reported. We developed a multiplexed and high-content screening assay using primary neurons and identified 67 small-molecule modulators of neuronal mitostasis (MnMs). Most MnMs that increased mitochondrial content, length, and/or health also increased mitochondrial function without altering neurite outgrowth. A subset of MnMs protected mitochondria in primary neurons from Aβ(1–42) toxicity, glutamate toxicity, and increased oxidative stress. Some MnMs were shown to directly target mitochondria. The top MnM also increased the synaptic activity of hippocampal neurons and proved to be potent in vivo, increasing the respiration rate of brain mitochondria after administering the compound to mice. Our results offer a platform that directly queries mitostasis processes in neurons, a collection of small-molecule modulators of mitochondrial dynamics and function, and candidate molecules for mitotherapeutics.

scholarly journals Mitochondrial Pathobiology and Metabolic Remodeling in Progression to Overt Systolic Heart Failure

2020 ◽  
Vol 9 (11) ◽  
pp. 3582
Author(s):  
Antoine H. Chaanine ◽  
Thierry H. LeJemtel ◽  
Patrice Delafontaine
Keyword(s):  
Heart Failure ◽  
Cardiac Myocyte ◽  
Ion Homeostasis ◽  
Systolic Heart Failure ◽  
Redox Balance ◽  
High Energy ◽  
Mitochondrial Morphology ◽  
Metabolic Remodeling ◽  
Dynamics And Function ◽  
And Function

The mitochondria are mostly abundant in the heart, a beating organ of high- energy demands. Their function extends beyond being a power plant of the cell including redox balance, ion homeostasis and metabolism. They are dynamic organelles that are tethered to neighboring structures, especially the endoplasmic reticulum. Together, they constitute a functional unit implicated in complex physiological and pathophysiological processes. Their topology in the cell, the cardiac myocyte in particular, places them at the hub of signaling and calcium homeostasis, making them master regulators of cell survival or cell death. Perturbations in mitochondrial function play a central role in the pathophysiology of myocardial remodeling and progression of heart failure. In this minireview, we summarize important pathophysiological mechanisms, pertaining to mitochondrial morphology, dynamics and function, which take place in compensated hypertrophy and in progression to overt systolic heart failure. Published work in the last few years has expanded our understanding of these important mechanisms; a key prerequisite to identifying therapeutic strategies targeting mitochondrial dysfunction in heart failure.

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