Mitochondrial network regulation and its potential interference with inflammatory signals in pancreatic beta cells

Abstract

Mitochondria fulfil multiple tasks in nutrient metabolism, energy production, redox homeostasis and stress response, and are essential for pancreatic beta cell function. The dynamism and health of the mitochondrial network is regulated by fission-and fusion-triggering factors and by a quality control system that removes dysfunctional organelles. Alongside the role of mitochondria in regulating apoptotic cell death mediated primarily via production of reactive oxygen species and release of cytochrome c, there is evidence of other links between mitochondria and inflammation that have implications for cell viability. This review briefly outlines two pathways that are potentially vital for pancreatic beta cell function. The first concerns the regulation of Parkin, a protein that acts, not only as a central player in regulating mitophagy, but also as an activator of the NF-ĸB pathway. The fact that expression of optic atrophy protein 1 (OPA1), a mitochondrial fusion inducer and master mitochondrial cristae biogenetic factor, is increased following NF-ĸB activation highlights a point of mitochondrial control that might be influenced by TNFα signalling. A second axis of interest is suggested by IL-6-mediated upregulation of the fission inducer FIS1 alongside downregulation of mitofusin 2 (MFN2), a guard of mitochondrial fusion and metabolism and an inhibitor of apoptosis. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied two other reviews on topics from this symposium (by Marc Donath,

Inhibition of Miro1 disturbs mitophagy and pancreatic β-cell function interfering insulin release via IRS-Akt-Foxo1 in diabetes

“…Mitochondrial function regulated by mitophagy is essential to preserve pancreatic beta cell function and insulin secretion. Impaired beta cell function, together with deficient mitophagy, are both associated with chronic inflammation and insulin resistance [3]. Thus, insulin resistance, inflammation and pancreatic cell dysfunction are common pathological events in obese individuals [4].…”

“…Although in-depth research has been done in this area, the occurrence of complex and associated cell events and related behaviors in vivo connecting mitochondrial function and perturbed insulin secretion in T2D are not well understood. Mitochondrial activity is necessary for the process of cell proliferation and metabolism, and mitochondrial dysfunction is associated with a variety of human diseases, including cancer [5], diabetes [3] and age-related diseases [6]. Increasing evidence suggests that mitophagy maintains mitochondrial integrity and quality control not only by selectively removing dysfunctional or damaged mitochondria [7][8][9], but also by promoting biosynthesis of new mitochondria [10].…”

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

“…Fehlerhafte Komponenten können so in nur wenigen Mitochondrien konzentriert und damit separiert werden. Anschließend werden solche Mitochondrien mittels Autophagie aus der Zelle beseitigt [12]. Hierdurch bleibt die Funktionsfähigkeit der Mitochondrien hoch und der Massenverlust gering.…”

“…Hierdurch bleibt die Funktionsfähigkeit der Mitochondrien hoch und der Massenverlust gering. Gleichzeitig kann durch eine unterschiedliche Häufigkeit von Fusionen einerseits und Teilungsprozessen andererseits die Struktur des mitochondrialen Netzwerks beeinflusst werden [11,12]. So können kleine kugelige Mitochondrien das Netzwerk dominieren oder sich lange filamentöse Strukturen ausbilden.…”

Islet inflammation in type 2 diabetes

“…This commentary on the 'Islet inflammation in type 2 diabetes' symposium at the EASD 2015 meeting focuses on a few general issues regarding the association between inflammation and the pancreatic islets in human type 2 diabetes. It is accompanied by articles that specifically address the mechanistic implications [19,20] and therapeutic perspectives [21].…”