Precise expression of Fis1 is important for glucose responsiveness of beta cells

Abstract

Mitochondrial network functionality is vital for glucose-stimulated insulin secretion in pancreatic beta cells. Altered mitochondrial dynamics in pancreatic beta cells are thought to trigger the development of type 2 diabetes mellitus. Fission protein 1 (Fis1) might be a key player in this process. Thus, the aim of this study was to investigate mitochondrial morphology in dependence of beta cell function, after knockdown and overexpression of Fis1. We demonstrate that glucose-unresponsive cells with impaired glucose-stimulated insulin secretion (INS1-832/2) showed decreased mitochondrial dynamics compared with glucose-responsive cells (INS1-832/13). Accordingly, mitochondrial morphology visualised using MitoTracker staining differed between the two cell lines. INS1-832/2 cells formed elongated and clustered mitochondria, whereas INS1-832/13 cells showed a homogenous mitochondrial network. Fis1 overexpression using lentiviral transduction significantly improved glucose-stimulated insulin secretion and mitochondrial network homogeneity in glucose-unresponsive cells. Conversely, Fis1 downregulation by shRNA, both in primary mouse beta cells and glucose-responsive INS1-832/13 cells, caused unresponsiveness and significantly greater numbers of elongated mitochondria. Overexpression of FIS1 in primary mouse beta cells indicated an upper limit at which higher FIS1 expression reduced glucose-stimulated insulin secretion. Thus, FIS1 was overexpressed stepwise up to a high concentration in RINm5F cells using the RheoSwitch system. Moderate FIS1 expression improved glucose-stimulated insulin secretion, whereas high expression resulted in loss of glucose responsiveness and in mitochondrial artificial loop structures and clustering. Our data confirm that FIS1 is a key regulator in pancreatic beta cells, because both glucosestimulated insulin secretion and mitochondrial dynamics were clearly adapted to precise expression levels of this fission protein. 230:1Mitochondrial dynamics and insulin secretion j schultz and others

Mitochondrial dynamics in type 2 diabetes: Pathophysiological implications

“…Type 2 diabetes was related to mitochondrial network fragmentation in myocardium and a large decrease in mfn1 expression. In another study, Schultz et al have confirmed that FIS1 is a key regulator in pancreatic β-cells [67] ; the authors found that both glucose-stimulated insulin secretion and mitochondrial dynamics were clearly adapted to produce precise expression levels of this fission protein.…”

The pathogenetic role of β-cell mitochondria in type 2 diabetes

“…MtDNA copy number in β-cells lacking Opa1 is unchanged, but the activity of complex IV is significantly decreased, perturbing glucose-stimulated ATP production and GSIS (Zhang et al 2011). It was found that glucose-unresponsive cells exhibit poorer mitochondrial dynamics than glucose-responsive cells (Schultz et al 2016). Overexpression of FIS1 in glucose-unresponsive cells restores GSIS, and the mitochondrial network becomes more homogeneous.…”

“…Overexpression of FIS1 in glucose-unresponsive cells restores GSIS, and the mitochondrial network becomes more homogeneous. In contrast, silencing of Fis1 in murine insulin-secreting cells lessens glucose responsiveness and a higher frequency of elongated, likely dysfunctional, mitochondria is encountered (Schultz et al 2016). The prohibitin proteins have also been suggested to play important roles in maintaining mitochondrial integrity and function.…”

Regulation der Beta-Zellen der Langerhans’schen Inseln des Pankreas

“…dass das Dynamin related protein 1 (Drp1) [13] und das Fission protein 1 (Fis1) [14], beides Proteine, die für die Teilung von Mitochondrien notwendig sind, in Beta-Zellen eine wesentliche Rolle spielen. Die Reduktion der Expression der genannten Proteine führte in Beta-Zellen nicht nur zu einer Strukturveränderung des mitochondrialen Netzwerks mit langen, ringförmigen und aggregierten Mitochondrien, sondern auch zu einer signifikanten Abnahme der glukoseinduzierten Insulinsekretion [13,14]. Neueste Ergebnisse deuten darauf hin, dass das mitochondriale Netzwerk einer Beta-Zelle auch dessen Glukose-Responsivität widerspiegelt [14].…”