Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release

Abstract

All forms of diabetes share the common etiology of insufficient pancreatic β-cell function to meet peripheral insulin demand. In pancreatic β-cells, mitochondria serve to integrate the metabolism of exogenous nutrients into energy output, which ultimately leads to insulin release. As such, mitochondrial dysfunction underlies β-cell failure and the development of diabetes. Mitochondrial regulation of β-cell function occurs through many diverse pathways, including metabolic coupling, generation of reactive oxygen species, maintenance of mitochondrial mass, and through interaction with other cellular organelles. In this chapter, we will focus on the importance of enzymatic regulators of mitochondrial fuel metabolism and control of mitochondrial mass to pancreatic β-cell function, describing how defects in these pathways ultimately lead to diabetes. Furthermore, we will examine the factors responsible for mitochondrial biogenesis and degradation and their roles in the balance of mitochondrial mass in β-cells. Clarifying the causes of β-cell mitochondrial dysfunction may inform new approaches to treat the underlying etiologies of diabetes.

Keywords: Diabetes; Islet; Metabolism; Mitochondria; Mitophagy; mtDNA.

Figure 1. Mitochondrial momentum is necessary for maintenance of insulin secretion and glucose control

(A) Schematic model of key contributors to mitochondrial momentum, adapted from Newton’s Second Law. (B) The outcomes of mitochondrial momentum resulting in normal β-cell function (with adequate mitochondrial mass and velocity). Reduced mitochondrial mass or velocity leads to poor mitochondrial momentum and insulin secretion, ultimately resulting in hyperglycemia and diabetes.

Figure 2. Regulators of β-cell fuel metabolism intersect at the mitochondria to control ATP generation and insulin secretion

Focused model of metabolism of principal fuel sources in β-cells (black boxes), metabolites (black text), and their key enzymatic regulators (bold black text) vital for fuel metabolism, ATP generation, and insulin secretion. The effects of allosteric activators or inhibitors on GDH activity are indicated with grey lines. GLS – glutaminase, GS – glutamine synthase, GDH – glutamate dehydrogenase, SCHAD – short-chain L-3-hydroxyacyl-CoA dehydrogenase, GCK – glucokinase, GAD – glutamic acid decarboxylase, SCFA – short-chain fatty acids, GABA – γ-aminobutyric acid

Figure 3. Clec16a regulates mitophagy

Schematic model of Clec16a control of Parkin-mediated mitophagy and autophagosome-lysosome fusion, via its interaction with, and stabilization of, the E3 ubiquitin ligase Nrdp1. Loss of Clec16a-Nrdp1 leads to an accumulation of unhealthy mitochondria due to unrestrained Parkin activity that are trapped and cannot complete mitophagy as a result of impaired autophagosome-lysosome fusion. Adapted (with permission) from Soleimanpour, et al. Cell, .