Mitochondrial Superoxide Production Negatively Regulates Neural Progenitor Proliferation and Cerebral Cortical Development

Hou, Yan; Ouyang, Xin; Wan, Ruiqian; Cheng, Heping; Mattson, Mark P.; Cheng, Ann‐Lii

doi:10.1002/stem.1213

Cited by 80 publications

(100 citation statements)

References 51 publications

(61 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent study showed that rapid bursts of superoxide radical anions called superoxide flashes, which are highly reactive reduced forms of molecular oxygen, were involved in regulating the self-renewal and differentiation of mouse embryonic neural progenitor cells (NPCs). Mitochondrial superoxide scavengers or mPTP inhibitors reduce the frequency of superoxide flashes and enhance NPC proliferation [82]. In contrast, increased superoxide flashes are necessary for the differentiation of mouse NPCs into cortical neurons, and inhibiting mPTP or scavenging mitochondrial ROS impairs differentiation [83].…”

Section: Figmentioning

confidence: 99%

Connecting Mitochondria, Metabolism, and Stem Cell Fate

Wanet

Arnould

Najimi

et al. 2015

Stem Cells and Development

254

216

View full text Add to dashboard Cite

As sites of cellular respiration and energy production, mitochondria play a central role in cell metabolism. Cell differentiation is associated with an increase in mitochondrial content and activity and with a metabolic shift toward increased oxidative phosphorylation activity. The opposite occurs during reprogramming of somatic cells into induced pluripotent stem cells. Studies have provided evidence of mitochondrial and metabolic changes during the differentiation of both embryonic and somatic (or adult) stem cells (SSCs), such as hematopoietic stem cells, mesenchymal stem cells, and tissue-specific progenitor cells. We thus propose to consider those mitochondrial and metabolic changes as hallmarks of differentiation processes. We review how mitochondrial biogenesis, dynamics, and function are directly involved in embryonic and SSC differentiation and how metabolic and sensing pathways connect mitochondria and metabolism with cell fate and pluripotency. Understanding the basis of the crosstalk between mitochondria and cell fate is of critical importance, given the promising application of stem cells in regenerative medicine. In addition to the development of novel strategies to improve the in vitro lineage-directed differentiation of stem cells, understanding the molecular basis of this interplay could lead to the identification of novel targets to improve the treatment of degenerative diseases.

show abstract

Section: Figmentioning

confidence: 99%

Connecting Mitochondria, Metabolism, and Stem Cell Fate

Wanet

Arnould

Najimi

et al. 2015

Stem Cells and Development

254

216

View full text Add to dashboard Cite

show abstract

“…A superoxide flash event is initiated with transient opening of putative mitochondrial permeability transition pore (mPTP) and requires an intact mitochondrial electron transport chain (ETC) [2]. Functionally, superoxide flashes participate in the regulation of metabolism, cell proliferation and differentiation, hyperosmotic, inflammatory and oxidative stress responses, and even in the process of aging [5][6][7][8][9][10].…”

mentioning

confidence: 99%

Regulation of superoxide flashes by transient and steady mitochondrial calcium elevations

Jian

Hou

Yin

et al. 2014

Sci. China Life Sci.

Self Cite

View full text Add to dashboard Cite

The mitochondria play essential roles in both intracellular calcium and reactive oxygen species signaling. As a newly discovered universal and fundamental mitochondrial phenomenon, superoxide flashes reflect transient bursts of superoxide production in the matrix of single mitochondria. Whether and how the superoxide flash activity is regulated by mitochondrial calcium remain largely unknown. Here we demonstrate that elevating mitochondrial calcium either by the calcium ionophore ionomycin or by increasing the bathing calcium in permeabilized HeLa cells increases superoxide flash incidence, and inhibition of the mitochondrial calcium uniporter activity abolishes the flash response. Quantitatively, the superoxide flash incidence is correlated to the steady-state mitochondrial calcium elevation with 1.7-fold increase per 1.0 F/F 0 of Rhod-2 signal. In contrast, large mitochondrial calcium transients (e.g., peak △F/F 0 ~2.8, duration ~2 min) in the absence of steady-state elevations failed to alter the flash activity. These results indicate that physiological levels of sustained, but not transient, mitochondrial calcium elevation acts as a potent regulator of superoxide flashes, but its mechanism of action likely involves a multi-step, slow-onset process. ) and reactive oxygen species (ROS) are important intracellular signaling molecules. The mitochondria play pivotal roles in both Ca 2+ handling and redox homeostasis. It also provides a stage for Ca 2+ and ROS to tango on. Ca 2+ modulates ROS homeostasis by regulating the ROS-generating and antioxidant systems, while ROS modify the components of the Ca 2+ signaling toolkit and reshape local and global Ca 2+ signal amplitudes and kinetics [1]. With the aid of a novel, reversible superoxide biosensor, mt-cpYFP, we recently discovered stochastic, discrete and transient superoxide production events, named superoxide flashes, in single mitochondria [2]. As a novel ROSgenerating activity, superoxide flash exists in isolated single mitochondria, cultured cells, ex vivo beating hearts and even living animals [2][3][4]. A superoxide flash event is initiated with transient opening of putative mitochondrial permeability transition pore (mPTP) and requires an intact mitochondrial electron transport chain (ETC) [2]. Functionally, superoxide flashes participate in the regulation of metabolism, cell proliferation and differentiation, hyperosmotic, inflammatory and oxidative stress responses, and even in the process of aging [5][6][7][8][9][10].Whether and how is superoxide flash activity intertwined with mitochondrial Ca 2+ signaling? Wang et al.[2] explored the relationship between Ca 2+ and superoxide flash in cardiac cells and found that superoxide flash frequency is unaltered by either a 2-fold increase or an abolition of Ca 2+ sparks. Hou et al. [5] found that elevating Ca 2+ or ROS

show abstract

“…Recent studies, in which the mitochondrial ROS sensitive probe mtcpYFP was claimed to detect superoxide production, allowed characterization of the mitochondrial input in oxidative state of proliferating [48] and differentiating NSPCs [29]. It has been shown, despite the weak basal superoxide signal, cultured proliferating cortical NSPCs exhibit spontaneous burst-like generation of mitochondrial superoxide anions (superoxide flashes) without global changes in intracellular ROS levels [48].…”

Section: Mitochondria-derived Rosmentioning

confidence: 99%

“…It has been shown, despite the weak basal superoxide signal, cultured proliferating cortical NSPCs exhibit spontaneous burst-like generation of mitochondrial superoxide anions (superoxide flashes) without global changes in intracellular ROS levels [48]. The supposed superoxide oscillation requires the opening of the mitochondrial permeability transition pore (mPTP) and activity of the electron transport chain.…”

Section: Mitochondria-derived Rosmentioning

confidence: 99%