Elsevier

Mitochondrion

Volume 49, November 2019, Pages 245-258
Mitochondrion

Review
Dynamic of mitochondrial network, cristae, and mitochondrial nucleoids in pancreatic β-cells

https://doi.org/10.1016/j.mito.2019.06.007Get rights and content

Highlights

  • Mitochondria as glucose sensor are impaired at various stages of type 2 diabetes progression.

  • Diabetic pathology is frequently reflected by fragmented mitochondrial network.

  • Diabetic pathology affects ultramorphology of cristae, typically by inflation.

  • Diabetic pathology may reduce number of nucleoids of mtDNA.

Abstract

Type 2 diabetes progression stems from dysfunction of β-cells, besides the peripheral insulin resistance. Mitochondria as glucose sensor and regulation center are impaired at various stages of this progression. Their biogenesis and functional impairment is reflected by altered morphology of the mitochondrial network and ultramorphology of cristae and mitochondrial DNA loci, termed nucleoids. Aspects of all above changes are reviewed here together with a brief introduction to proteins involved in mitochondrial network dynamics, cristae shaping, and mtDNA nucleoid structure and maintenance. Most frequently, pathology is reflected by the fragmentation of network, cristae inflation or absence and declining number of nucleoids.

Introduction

Pancreatic islets (PI) and notably β-cells represent the endocrine pancreas, a center of regulation of glucose homeostasis for the organism. Numerous physiological and pathological aspects are still unknown, such as a time course of their biogenesis, existence of de novo differentiation of stem cells into β-cells in adult organism, as well as the initial events leading to a vicious spiral of type 2 diabetes development (Ježek et al., 2019a). Indeed the type 2 diabetes becomes a world-wide epidemic disease. Its etiology comprises not only the peripheral insulin resistance, i.e., impaired response to insulin of tissues like skeletal muscle, white adipose tissue, or liver, but involves also the dysfunction of β-cells. Progress in the β-cell pathology during the type 2 diabetes development proceeds in numerous steps. This begins by prediabetic states and extends to the increasing β-cell dysfunction and decreasing number of β-cells, notably by their dedifferentiation and transdifferentiation. Initial events include compensation responses of β-cells, their reversal upon progression and the accompanied low-grade PI inflammation (Ježek et al., 2019a). Mutual interaction of factors secreted or located on the surface of deterioriated β-cells with immune system and peripheral organs leads to the peripheral insulin resistance. In later stages of type 2 diabetes the key aspects accelerate to develop pathological states even more. These aspects include profound oxidative stress, lipotoxicity and glucotoxicity, all affecting β-cells.

Since the canonical mechanism of glucose-stimulated insulin secretion (GSIS) is based on the increased oxidative phosphorylation in the β-cell mitochondrion, its dysfunction and impairment of the physiological regulations involved leads to type 2 diabetes. When any mechanisms of energy production, metabolic regulations, and information signaling relevant to the mitochondrial physiology are disturbed, resulting dysfunction abolishes GSIS. Hence not only insults having the direct effects, but also those having the indirect effect become transferred to the progressive development of type 2 diabetes. Direct insults inhibit the oxidative phosphorylation, while the indirect effects are related to proteins shaping mitochondrial morphology and proper biogenesis/degradation balance. All these essential functions must be intact in the mitochondrion, otherwise a pathological state is developed.

Physiologically, ATP elevation leads to the closure of the plasma mebrane ATP-sensitive K+ channel, inducing the calcium influx to the cell cytosol in concert with other channels. This finally triggers exocytosis of insulin granules. All these processes are subjected to delicate regulations. Insulin exocytosis is also induced by numerous other mechanisms, which is out scope of this review (but see Ježek et al., 2019a). Nevertheless, any pathological state is likely to be reflected by the altered mitochondrial network morphology and altered cristae ultramorphology. In addition, concomitant impaired biogenesis of mitochondrion, mutations of mitochondrial DNA (mtDNA), and impairment of mtDNA gene expression and maintenance machinery leads also to the pathological changes of the entities termed nucleoids (Ježek et al., 2019b). Nucleoids are nucleoprotein complexes representing discrete and multiple (~1000 per cell) sites of mtDNA locations.

In this review, we attempted to briefly describe the knowledge on pathological relations of the mitochondrial network, mitochondrial cristae and nucleoid morphology. Morphological alternations may be either causes or consequences of the type 2 diabetes pathology. For each morphology level, we provide first a brief review of factors determining the physiologically normal morphology. When possible, details are explained using the available reports on pancreatic β-cells. Next, we describe possible changes, in order to understand the observed pathological changes. In this way, we summarize the available literature concerning mitochondrial morphology of pancreatic β-cells in relation to normal and diabetic states. Despite the fact that a morphological diagnostics would be plausible only for PI intended for transplantation, the knowledge of morphological alternations is very important, since they reflect the key pathological changes in pancreatic β-cells.

Section snippets

β-Cell mitochondrion

Mitochondrion is indeed the most appropriate term for the organelle representing the bioenergetics, metabolic, and informational regulatory center of the cell. Plural, i.e. “mitochondria”, has been historically derived from inspections of transmission electron microscopy (TEM) sections of the mitochondrial network, such as in the pioneer work of Palade (1964). The term “mitochondria” naturally corresponds to the artificially cut mitochondrial network upon the typical isolation of the organelle.

Compartments of mitochondrion

The complex structure of the IMM comprises the two major parts (Fig. 5A): i) the inner boundary membrane (IBM), which is parallel to OMM, thus being nearly cylindrical in tubules; and, ii) mitochondrial cristae, representing long protrusions (Kukat et al., 2015; Sun et al., 2007) with rather sharp edges at metabolic rich conditions (Fig. 5A; see Section 3.4). Cristae are often perpendicular to OMM (Pernas and Scorrano, 2016; Plecitá-Hlavatá and Ježek, 2016). Such canonical IMM morphology

Nucleoids of mtDNA

An autonomous robust genome is present in the mitochondrion. Its influence on cell physiology and pathology is much higher than would be judged from its small size. Mitochondrial DNA is intron-free. Its expression proceeds through its own genetic code. mtDNA is circular double-stranded molecule, highly packed with a density found typically in prokaryotes (Gustafsson et al., 2016). The robustness of the mtDNA genome is given by the presence of mtDNA in multiple copies in a single cell, typically

Future perspectives

Understanding of a self-identity checking for pancreatic β-cells, their information signaling to the periphery, notably during the low-grade inflammation of pancreatic islets, and knowledge of other molecular events during the progressive type 2 diabetes development are required to understand the etiology of this disease and design novel ways to cure it. The concomitant understanding of mitochondrial pathology is an integral part of these efforts. In order to proceed in deeper insight, the use

Declaration of Competing Interest

Both authors have no competing interests to declare.

Acknowledgements

This work was supported by the Grant Agency of the Czech Republic grant number 17-08565S and 17-01813S.

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