Isoplumbagin (isoPLB, 5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone, has been observed to exercise anti-inflammatory, antimicrobial, and antineoplastic activities. Notably, whether and how isoPLB, plumbagin (PLB), or other related compounds impact transmembrane ionic currents is not entirely clear. In this study, during GH3-cell exposure to isoPLB, the peak and sustained components of an erg (ether-à-go-go related gene)-mediated K+ current (IK(erg)) evoked with long-lasting-step hyperpolarization were concentration-dependently decreased, with a concomitant increase in the decaying time constant of the deactivating current. The presence of isoPLB led to a differential reduction in the peak and sustained components of deactivating IK(erg) with effective IC50 values of 18.3 and 2.4 μM, respectively, while the KD value according to the minimum binding scheme was estimated to be 2.58 μM. Inhibition by isoPLB of IK(erg) was not reversed by diazoxide; however, further addition of isoPLB, during the continued exposure to 4,4′-dithiopyridine, did not suppress IK(erg) further. The recovery of IK(erg) by a two-step voltage pulse with a geometric progression was slowed in the presence of isoPLB, and the decaying rate of IK(erg) activated by the envelope-of-tail method was increased in its presence. The strength of the IK(erg) hysteresis in response to an inverted isosceles-triangular ramp pulse was diminished by adding isoPLB. A mild inhibition of the delayed-rectifier K+ current (IK(DR)) produced by the presence of isoPLB was seen in GH3 cells, while minimal changes in the magnitude of the voltage-gated Na+ current were demonstrated in its presence. Moreover, the IK(erg) identified in MA-10 Leydig tumor cells was blocked by adding isoPLB. Therefore, the effects of isoPLB or PLB on ionic currents (e.g., IK(erg) and IK(DR)) demonstrated herein would be upstream of our previously reported perturbations on mitochondrial morphogenesis or respiration. Taken together, the perturbations of ionic currents by isoPLB or PLB demonstrated herein are likely to contribute to the underlying mechanism through which they, or other structurally similar compounds, result in adjustments in the functional activities of different neoplastic cells (e.g., GH3 and MA-10 cells), presuming that similar in vivo observations occur.

As mitochondrial dysfunction has increasingly been implicated in neurological diseases, much of the investigation focuses on the response of the mitochondria. It appears that mitochondria can respond to external stimuli speedy fast, in seconds. Understanding how mitochondria sense the signal and communicate with cytosolic pathways are keys to understand mitochondrial regulation in diseases or in response to trauma. It was not until recently that a novel mitochondrial protein, phosphoglycerate mutase family member 5 (PGAM5) has emerged to be a new regulator of mitochondrial homeostasis. Although controversial results reveal beneficial as well as detrimental roles of PGAM5 in cancers, these findings also suggest PGAM5 may have diverse regulation on cellular physiology. Roles of PGAM5 in neuronal tissues remain to be uncovered. This review discusses current knowledge of PGAM5 in neurological diseases and provides future perspectives.

StatementThis study reveals a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma cells involving PIP3, whose depletion with PTEN rescues myoblast fusion defects.3 Abstract Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. While the transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs, and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.

Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. Although transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.